{"gene":"NR5A2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1991,"finding":"FTZ-F1 is a member of the nuclear hormone receptor superfamily that binds the zebra element of the fushi tarazu (ftz) gene and activates ftz transcription, particularly in stripes 1, 2, 3, and 6 of the Drosophila embryo.","method":"cDNA cloning by recognition site screening, immunological cross-reaction, peptide sequence analysis, DNA binding assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cloning and biochemical identification, replicated across multiple subsequent studies","pmids":["1709303"],"is_preprint":false},{"year":1992,"finding":"FTZ-F1 contains a conserved 30-amino-acid basic region (the FTZ-F1 box) C-terminal to the zinc finger motif; gel mobility shift competition assays showed the FTZ-F1 box governs recognition of the first three bases of the binding sequence (5'-PyCAAGGPyCPu-3') while the zinc finger recognizes the remainder, and FTZ-F1 binds DNA as a monomer.","method":"Gel mobility shift competition with mutant peptides, gel mobility shift matrix competition assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical mutagenesis with multiple orthogonal binding assays, conserved across species (fruit fly, silkworm, mouse)","pmids":["1448096"],"is_preprint":false},{"year":1992,"finding":"Mouse ELP (embryonal long terminal repeat-binding protein) is a homolog of Drosophila FTZ-F1, both sharing conserved DNA-binding and putative ligand-binding domains and recognizing the same non-repeat DNA sequence element, functioning in undifferentiated embryonal carcinoma cells.","method":"cDNA cloning, sequence analysis, DNA binding assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sequence and binding analysis across two species, single lab","pmids":["1545809"],"is_preprint":false},{"year":1993,"finding":"A developmental isoform of FTZ-F1 (beta FTZ-F1) is expressed from a mid-prepupal chromosome puff (75CD) in Drosophila and binds over 150 chromosomal targets including late prepupal puffs, implicating it as a regulator of insect metamorphosis downstream of ecdysone.","method":"cDNA cloning, indirect immunofluorescent staining on polytene chromosomes","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct chromosomal binding demonstrated by immunofluorescence, single lab","pmids":["8096644"],"is_preprint":false},{"year":1994,"finding":"FTZ-F1 alpha and FTZ-F1 beta both bind as monomers to the 9-bp F1RE in the ftz zebra element with similar affinities and sequence specificities, and both contribute to net transcriptional activity; they do not form heterodimers with each other.","method":"In vitro DNase I footprinting, gel mobility shift with recombinant proteins and N-terminally truncated receptors, cotransfection reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with recombinant proteins, footprinting, and functional cotransfection, multiple orthogonal methods","pmids":["8164672"],"is_preprint":false},{"year":1996,"finding":"Rat FTF (fetoprotein transcription factor, ortholog of NR5A2) is an orphan nuclear receptor of the FTZ-F1 family that recognizes the DNA sequence 5'-TCAAGGTCA-3' and activates the alpha1-fetoprotein (AFP) promoter; it binds DNA as a monomer without requiring a specific ligand, and C-terminus-truncated FTF exerts dominant negative effects.","method":"cDNA cloning, DNA binding assays, transient transfection with deletion/truncation mutants, Kd measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro binding quantification, dominant-negative mutagenesis, and transcriptional activation assays in a single paper","pmids":["8668203"],"is_preprint":false},{"year":1996,"finding":"The mammalian ftz-f1 gene (encoding Ad4BP/SF-1) contains an intronic Ad4 site to which Ad4BP itself binds, creating an autoregulatory loop that maintains high expression specifically in steroidogenic tissues; DNase I hypersensitivity showed this chromatin region is 'open' in adrenal and Y-1 cells but 'closed' in liver.","method":"Gel mobility shift assay, DNase I footprinting, DNase I hypersensitivity, site-directed mutagenesis, transient transfection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, chromatin analysis, and functional reporter assays","pmids":["8626518"],"is_preprint":false},{"year":1996,"finding":"FTZ-F1 directly regulates the pupal cuticle gene EDG84A in Drosophila: heat-induction of FTZ-F1 causes premature EDG84A expression; mutation of the FTZ-F1 binding site in the EDG84A promoter abolishes reporter expression in transgenic flies.","method":"Heat-shock induction of FTZ-F1 transgene, lacZ reporter transgenics, base substitution mutagenesis of FTZ-F1 binding site","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vivo gain-of-function and promoter mutagenesis in transgenic Drosophila","pmids":["8887679"],"is_preprint":false},{"year":1997,"finding":"Ftz-F1 (nuclear hormone receptor) and the homeodomain protein Ftz are present in a complex in Drosophila embryos; Ftz-F1 facilitates binding of Ftz to DNA and allows Ftz to interact with weak-affinity sites; embryos lacking Ftz-F1 display ftz-like pair-rule defects and fail to activate Ftz target genes despite Ftz being expressed.","method":"Co-immunoprecipitation from Drosophila embryo extracts, in vitro DNA binding facilitation assays, genetic analysis of ftz-f1 mutants","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal biochemical interaction plus in vivo genetic validation, two independent concurrent papers (PMID 9020364, 9020363)","pmids":["9020364","9020363"],"is_preprint":false},{"year":1997,"finding":"Ftz and Ftz-F1 interact directly and specifically in vitro and in vivo through a conserved domain in Ftz; Ftz-F1 is an obligatory maternal cofactor for Ftz function in Drosophila segmentation.","method":"In vitro binding assays, in vivo genetic rescue experiments, domain mapping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct protein interaction established in vitro and validated in vivo, replicated concurrently by two independent labs","pmids":["9020363","9020364"],"is_preprint":false},{"year":1997,"finding":"Ftz-F1 and Ftz cooperate to activate the engrailed gene via adjacent conserved binding sites in an engrailed enhancer; Ftz-F1 and Ftz bind these sites with 4- to 8-fold cooperativity, suggesting direct protein-protein contact.","method":"DNase I footprinting, gel mobility shift assay, transgenic reporter analysis, genetic epistasis","journal":"Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — cooperative DNA binding demonstrated biochemically, validated by in vivo reporter and genetics","pmids":["9043065"],"is_preprint":false},{"year":1998,"finding":"Human NR5A2 (hB1F) is an orphan nuclear receptor of the FTZ-F1 family that specifically binds the B1 region of hepatitis B virus enhancer II (ENII) and trans-activates ENII; mapped to chromosome 1q31-32.1; a splice isoform hB1F-2 with an extra 46 amino acids in the A/B region was identified.","method":"Yeast one-hybrid screening, DNA binding assays, transactivation reporter assays, RT-PCR, FISH","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding and transactivation demonstrated with multiple assays, foundational characterization of human NR5A2","pmids":["9786908"],"is_preprint":false},{"year":1999,"finding":"Beta FTZ-F1 (Drosophila ortholog of NR5A2) functions as a competence factor for stage-specific responses to ecdysone during metamorphosis; beta FTZ-F1 mutants cannot respond properly to the prepupal ecdysone pulse and the ecdysone-triggered genetic hierarchy is severely attenuated, though ecdysone receptor expression is unaffected.","method":"Genetic analysis of beta FTZ-F1 loss-of-function mutants, molecular analysis of downstream ecdysone target gene expression","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined molecular phenotype, epistasis placing beta FTZ-F1 upstream of ecdysone-response hierarchy","pmids":["10078197"],"is_preprint":false},{"year":2001,"finding":"The Ftz-F1/Ftz interaction involves two surfaces: the Ftz-F1 DNA-binding domain interacts strongly with Ftz and facilitates Ftz binding to target DNA; the AF-2 domain of Ftz-F1 interacts with an LRALL sequence in Ftz (resembling nuclear receptor coactivator LXXLL motifs); murine SF-1 functionally substitutes for Drosophila Ftz-F1 in vivo, demonstrating evolutionary conservation.","method":"In vitro pulldown/binding assays, domain mapping with truncation mutants, in vivo genetic rescue experiments in Drosophila","journal":"Mechanisms of development","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of interaction domains plus in vivo genetic rescue, multiple orthogonal methods","pmids":["11520662"],"is_preprint":false},{"year":2001,"finding":"Ftz acts as an LXXLL motif-dependent coactivator for the orphan receptor FTZ-F1: the Ftz LXXLL motif and FTZ-F1 AF-2 core/LBD are required for interaction as shown by mammalian two-hybrid assays; this interaction is required for FTZ-F1 activation of target genes in Drosophila embryos and for the cuticle phenotype.","method":"Mammalian one- and two-hybrid assays, LXXLL motif mutagenesis, transgenic fly analysis of target gene expression and cuticle phenotype","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — domain mutagenesis with in vivo validation in transgenic Drosophila","pmids":["11592991"],"is_preprint":false},{"year":2003,"finding":"Human LRH-1/hB1F (NR5A2) and HNF1 directly interact in vitro and synergize to activate hepatitis B virus enhancer II (ENII) and initiate viral gene transcription and DNA replication even in non-hepatic cells; specific activation domains in both proteins contribute to this synergism.","method":"In vitro protein interaction assays, cotransfection reporter assays in non-hepatic cells, domain mapping","journal":"Cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein interaction and functional synergism demonstrated, single lab","pmids":["14728801"],"is_preprint":false},{"year":2004,"finding":"The homeodomain protein Prox1 functions as a co-repressor for human LRH-1 (NR5A2), demonstrating functional conservation of Drosophila Ftz/Ftz-F1 homeodomain–nuclear receptor interaction in vertebrates; Prox1 represses LRH-1 transcriptional activity in the enterohepatic system.","method":"Protein interaction assays, cotransfection reporter assays, characterization in liver cell lines","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and functional repression shown, single lab, limited orthogonal methods described in abstract","pmids":["15143342"],"is_preprint":false},{"year":2005,"finding":"Crystal structure of the human LRH-1 (NR5A2) DBD-DNA complex at 2.2 Å shows the Ftz-F1 box folds into a novel helix that packs against the DBD but does not directly contact DNA; mutations disrupting Ftz-F1 helix positioning do not eliminate DNA binding but significantly reduce transcriptional activity and eliminate GRIP1 coactivator enhancement, revealing long-range DBD→LBD functional communication.","method":"X-ray crystallography, site-directed mutagenesis, transcriptional reporter assays, coactivator recruitment assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and functional assays in one study","pmids":["16289203"],"is_preprint":false},{"year":2006,"finding":"Beta FTZ-F1 potentiates ecdysone receptor (EcR) activity by recruiting a p160/SRC coactivator (FISC) through direct protein-protein interaction; this interaction dramatically increases FISC recruitment to the functional ecdysone receptor in a 20E-dependent manner, enhances local histone H4 acetylation, and drives stage-specific 20E effector gene expression during mosquito reproduction.","method":"Protein-protein interaction assays, ChIP, histone acetylation analysis, gene expression analysis in vivo","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction plus ChIP plus histone modification analysis, multiple orthogonal methods","pmids":["17015464"],"is_preprint":false},{"year":2006,"finding":"NR5A2 knockout mice display embryonic lethality around gastrulation: NR5A2-/- embryos show primitive streak formation failure and inability to generate embryonic or extraembryonic mesoderm; tetraploid complementation showed NR5A2 is required in extraembryonic tissues for epiblast gastrulation.","method":"Targeted gene disruption (knockout mice), morphological analysis, marker gene expression, tetraploid complementation aggregation experiments","journal":"Developmental dynamics","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional rescue experiment (tetraploid complementation) plus full phenotypic characterization","pmids":["17075876"],"is_preprint":false},{"year":2007,"finding":"Nr5a2 heterozygous female mice show reduced fertility arising from decreased circulating progesterone and impaired luteal function, without defects in follicular development, ovulation, or estrogen production; exogenous progesterone supplementation rescues reproductive ability, establishing Nr5a2 as an in vivo regulator of luteal steroidogenesis.","method":"Nr5a2+/- mice, hormone measurements, progesterone rescue experiment, reproductive outcome assessment","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with pharmacological rescue, direct causal link between Nr5a2 dose and progesterone production","pmids":["17409375"],"is_preprint":false},{"year":2010,"finding":"Nr5a2 (LRH-1) can replace Oct4 in the reprogramming of mouse somatic cells to iPSCs; sumoylation mutants of Nr5a2 with enhanced transcriptional activity further increase reprogramming efficiency; genome-wide location analysis shows Nr5a2 shares common gene targets with Sox2 and Klf4; Nr5a2 activates Nanog as part of its reprogramming mechanism.","method":"Retroviral reprogramming assay, sumoylation site mutagenesis, genome-wide ChIP-chip location analysis, Nanog reporter and expression analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional replacement assay, genome-wide binding analysis, and mechanistic follow-up via Nanog activation","pmids":["20096661"],"is_preprint":false},{"year":2011,"finding":"Small molecule agonists of LRH-1/NR5A2 can bind its ligand-binding domain; crystal structure of LRH-1 LBD bound to a synthetic agonist defined the binding pocket and guided structure-activity relationship studies yielding LRH-1-selective (RJW101) and dual LRH-1/SF-1 agonists (RJW100) with activity at endogenous target genes in human cell lines.","method":"X-ray crystallography of LBD-ligand complex, peptide recruitment assay, structure-activity relationship medicinal chemistry, endogenous gene expression assays","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation in human cells, multiple agonist series characterized","pmids":["21391689"],"is_preprint":false},{"year":2012,"finding":"Drosophila FTZ-F1 interacts with juvenile hormone receptor candidates MET and GCE in a JH-dependent manner via AF-2/LXXLL (LIXXL) interaction; removal of FTZ-F1 helix 12 (AF2) severely reduces interaction; the interaction relies on hydrophobic contacts including a unique interaction with helix 4, without requiring canonical charge clamp residues.","method":"Insect two-hybrid assays, homology modeling, docking simulations, domain deletion analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid assays with domain analysis, supported by modeling, single lab","pmids":["22249180"],"is_preprint":false},{"year":2013,"finding":"Nr5a2 conditional deletion in the pancreas leads to destabilization of mature acinar differentiation, acinar-to-ductal metaplasia, loss of regenerative capacity after pancreatitis, and dramatically accelerates Kras-driven acinar-to-ductal metaplasia and PDA precursor development.","method":"Conditional knockout mice (PdxCre-late; Nr5a2 c/c), caerulein pancreatitis model, histology, marker analysis","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout with multiple disease models, replicated findings across two concurrent labs (PMID 23645620, 23598351)","pmids":["23645620"],"is_preprint":false},{"year":2013,"finding":"Nr5a2 haploinsufficiency sensitizes the pancreas to caerulein-induced damage with increased acino-ductal metaplasia, impaired recovery, myeloid cell infiltration, and proinflammatory cytokine expression with hyperactivation of NF-κB and STAT3; a single acute pancreatitis episode cooperates with Kras(G12V) to accelerate preneoplastic lesion development.","method":"Nr5a2+/- and conditional Nr5a2 epithelial-specific knockout mice, caerulein pancreatitis model, molecular pathway analysis (NF-κB, STAT3)","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model with molecular pathway analysis, replicated across two concurrent publications","pmids":["23598351"],"is_preprint":false},{"year":2013,"finding":"Drosophila Ftz-f1 is SUMOylated in vitro and in vivo; SUMO levels regulate Ftz-f1 expression, and Ftz-f1 in turn drives expression of scavenger receptor Snmp1, which mediates lipid uptake in steroidogenic tissues for ecdysteroid biosynthesis.","method":"In vitro and in vivo SUMOylation assays, RNAi knockdown in Drosophila, lipid staining, hormone titer measurements, genetic epistasis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo SUMOylation demonstrated with functional genetic epistasis, single lab","pmids":["23637637"],"is_preprint":false},{"year":2014,"finding":"LRH-1 (NR5A2) initiates an ER stress resolution pathway independent of canonical UPR: in response to ER stress, LRH-1 induces expression of kinase Plk3, which phosphorylates and activates transcription factor ATF2; hepatic Lrh-1-null mice cannot resolve ER stress, and restoring Plk3 rescues ER stress resolution in Lrh-1-null cells; LRH-1 agonist treatment increases ER stress resistance.","method":"Hepatic conditional Lrh-1 knockout mice, Plk3 knockout mice, viral rescue of Plk3, ATF2 manipulation, ER stress induction assays, LRH-1 agonist treatment","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (KO, rescue) defining a novel pathway with pharmacological validation","pmids":["24737860"],"is_preprint":false},{"year":2014,"finding":"Nr5a2 granulosa-specific depletion prevents ovulation (at least partly through downregulation of the progesterone receptor gene Pgr) and impairs luteal function with reduced progesterone synthesis due to defects in cholesterol transport (down-regulation of Scarb1, Ldlr, Star).","method":"Conditional knockout mice (Nr5a2-Cyp19-Cre), hormone measurements, gene expression analysis, pseudopregnancy test","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with mechanistic pathway analysis linking Nr5a2 to cholesterol transport genes and progesterone synthesis","pmids":["24552399"],"is_preprint":false},{"year":2014,"finding":"NR5A2 is required during pancreatic organogenesis for expansion of nascent pancreatic epithelium, formation of multipotent progenitor cells, and acinar differentiation; NR5A2 directly controls expression and regulatory interactions with PTF1A, MYC, GATA4, FOXA2, RBPJL, and MIST1; Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and bind shared regulatory regions of pancreatic genes.","method":"Conditional gene inactivation, genome-wide binding analysis (ChIP), expression analysis, co-binding analysis at shared regulatory regions","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO plus genome-wide ChIP establishing direct target relationships and co-regulatory interactions","pmids":["25063451"],"is_preprint":false},{"year":2014,"finding":"TNF suppresses intestinal glucocorticoid synthesis by activating c-Jun and NF-κB, both of which physically interact with NR5A2 and repress Cyp11a1 reporter activity; dominant-negative JNK1 or IκB relieves repression; NR5A2 activity is thus antagonized by inflammatory signals to sustain chronic colitis.","method":"Reporter assays, protein interaction (c-Jun/NF-κB with NR5A2), dominant-negative experiments, mouse colitis model with TNF inhibitor rescue","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein-protein interaction with functional reporter assays and in vivo mouse model rescue","pmids":["24570488"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human LRH-1 (NR5A2) LBD bound by PIP3 (PI(3,4,5)P3) at high affinity; the hydrophobic PIP3 tails are buried inside the LBD ligand-binding pocket while the negatively charged PIP3 head group is presented on the receptor surface, similar to PIP3-SF-1 binding mode; PIP3 binding stabilizes the LRH-1 LBD.","method":"X-ray crystallography of LBD-PIP3 complex, binding affinity measurement, thermal stability assay","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation, extends prior SF-1 structural data to NR5A2","pmids":["26416531"],"is_preprint":false},{"year":2016,"finding":"NR5A2 controls neural stem cell fate decisions: overexpression promotes neurogenesis and inhibits astrogliogenesis; loss-of-function delays neuronal differentiation; NR5A2 directly regulates the Ink4/Arf locus, Prox1, Notch1 and JAK/STAT signaling; upstream regulation of NR5A2 involves proneural genes, Notch1, and JAK/STAT pathways.","method":"Overexpression and shRNA knockdown in primary neural stem cells and mouse embryos in utero, target gene expression analysis, pathway analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss- and gain-of-function with multiple target pathway analyses, in vivo and in vitro validation","pmids":["27447294"],"is_preprint":false},{"year":2016,"finding":"In zebrafish, nr5a2 (ortholog of mammalian NR5A2) is required for acinar cell differentiation of the exocrine pancreas and for hepatic progenitor outgrowth and differentiation; chemical inhibition of Nr5a2 during hepatopancreas progenitor specification disrupts exocrine pancreas formation and enhances liver size, indicating Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice.","method":"Targeted genetic null mutant in zebrafish, chemical antagonist (Cpd3) temporal inhibition, marker gene analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null plus temporally controlled chemical inhibition dissecting iterative roles","pmids":["27474396"],"is_preprint":false},{"year":2017,"finding":"Nr5a2 is essential for granulosa cell proliferation: conditional knockout reduces proliferation (assessed by BrdU, PCNA, FACS); downregulates cyclin transcripts (Ccnd1, Ccnd2, Ccne1, Ccne2, E2f1, E2f2); pharmacological inhibition by ML180 reverse agonist or β-catenin inhibition similarly decreases cyclin transcripts, identifying β-catenin as an Nr5a2 cofactor in this process.","method":"Conditional knockout (Nr5a2-Amhr2-Cre), BrdU incorporation, PCNA immunostaining, FACS, microarray, ML180 pharmacological inhibition, β-catenin inhibitor treatment","journal":"Journal of the Endocrine Society","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with pharmacological corroboration and mechanistic pathway analysis","pmids":["29379893"],"is_preprint":false},{"year":2017,"finding":"LRH-1 (NR5A2) directly binds to LRH-1 binding sites in the FASLG (CD95L/FasL) promoter and drives FASLG promoter activity in T cells; mutation of LRH-1 binding sites reduces FASLG promoter activity; pharmacological inhibition of LRH-1 decreases activation-induced FasL expression and FasL-mediated T cell apoptosis and cytotoxicity.","method":"Chromatin immunoprecipitation, promoter reporter assays with binding site mutagenesis, pharmacological inhibition, T cell functional assays, mouse hepatitis model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP plus mutagenesis plus in vivo pharmacological model, multiple orthogonal methods","pmids":["28406481"],"is_preprint":false},{"year":2018,"finding":"NR5A2 undergoes transcriptional relocation in Nr5a2+/- pancreatic tissue from differentiation-specific to inflammatory gene promoters; this promotes AP-1-dependent inflammatory gene transcription; pancreatic deletion of Jun rescues the pre-inflammatory phenotype and NR5A2 binding to inflammatory gene promoters; NR5A2 thus links differentiation and inflammatory programs.","method":"Global transcriptomic analysis, ChIP in pancreatic tissue, conditional Jun knockout rescue, NR5A2 ChIP-seq","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq with genetic rescue (Jun KO) and transcriptomics, multiple orthogonal approaches","pmids":["29443959"],"is_preprint":false},{"year":2019,"finding":"LRH-1/NR5A2 is required for T cell maturation and function: T cell-specific deletion causes drastic loss of mature peripheral T cells, strongly reduced activation-induced proliferation in vitro and in vivo, and failure to control viral infections by CD8+ T cells; LRH-1 is induced in T lymphocytes upon stimulation.","method":"T cell-specific LRH-1 conditional knockout mice, T cell proliferation assays, antigen immunization, viral infection challenge","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with multiple in vitro and in vivo functional readouts","pmids":["31328159"],"is_preprint":false},{"year":2020,"finding":"NR5A2 synergizes with coactivator NCOA3 to upregulate NRF2 expression, thereby preventing BET inhibitor (BETi)-induced ferroptosis in breast cancer cells; inhibition of NR5A2 or NCOA3 enhances BETi anti-cancer effects in vitro and in vivo.","method":"siRNA knockdown, overexpression, small molecule inhibitors, Western blot, in vivo xenograft model","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — functional assays in multiple systems but interaction between NR5A2 and NCOA3 not biochemically reconstituted in abstract","pmids":["32536370"],"is_preprint":false},{"year":2020,"finding":"LRH-1/NR5A2 inhibition reduces LPS-induced pro-inflammatory cytokine production in macrophages by downregulating LRH-1 targets glucokinase and glutaminase-2, thereby impairing mitochondrial ATP production and LPS-induced macrophage activation; in vivo LRH-1 inhibition reduces TNF production and liver damage in macrophage-dependent hepatitis.","method":"LRH-1 pharmacological inhibition, siRNA knockdown, metabolic assays (mitochondrial ATP), cytokine measurement, mouse hepatitis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic loss-of-function with mechanistic metabolic readout, single lab","pmids":["32111818"],"is_preprint":false},{"year":2021,"finding":"Nr5a2 depletion from granulosa cells of primordial follicles impairs activation of primordial follicles into the growing pool: cKO ovaries have more primordial and fewer primary follicles; Nr5a2 loss induces changes in quiescence markers, follicle activation inhibitors, and regulators of migration/EMT.","method":"Conditional knockout from primordial follicles, follicle enumeration, in vitro culture, RNA sequencing","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with transcriptomic analysis, single lab","pmids":["33441767"],"is_preprint":false},{"year":2021,"finding":"The combined activity of Esrrb and Nr5a2 is essential for naïve mouse ESC self-renewal: double depletion causes pluripotency network collapse and differentiation; Esrrb and Nr5a2 co-occupy a large common set of regulatory elements and control binding of Oct4, Sox2, and Nanog to DNA.","method":"Conditional double knockout in ESCs, ChIP-seq, transcriptome analysis","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq showing mechanistic control of pluripotency factor binding","pmids":["34397088"],"is_preprint":false},{"year":2022,"finding":"NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway in pancreatic islets: LRH-1 ablation in beta cells blocks beta cell proliferation and abolishes agonist (BL001) anti-diabetic action; LRH-1 activation induces PTGS2/COX2 expression, increasing PGE2 levels; PGE2 acts via PTGER1 receptor to confer islet survival against cytokine-induced apoptosis.","method":"Beta cell-specific conditional knockout, agonist (BL001) treatment, PTGS2 inhibition, PTGER1 antagonist, cytochrome c release, PARP cleavage assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO combined with pharmacological dissection defining a multi-step signaling pathway","pmids":["35602948"],"is_preprint":false},{"year":2022,"finding":"Nr5a2 is an essential pioneer factor for zygotic genome activation (ZGA) in mouse two-cell embryos: Nr5a2 is required for progression beyond the two-cell stage; it binds its motif within SINE B1/Alu retrotransposable elements in cis-regulatory regions of ZGA genes; NR5A2 promotes chromatin accessibility during ZGA and binds nucleosomal DNA in vitro; chemical inhibition indicates 72% of ZGA genes are regulated by Nr5a2.","method":"De novo motif search, Nr5a2 knockout in mouse embryos, ATAC-seq (chromatin accessibility), ChIP/CUT&RUN in embryos, in vitro nucleosome binding assays, chemical inhibition","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic KO plus in vitro nucleosome binding plus genome-wide chromatin accessibility, multiple orthogonal methods","pmids":["36423263"],"is_preprint":false},{"year":2023,"finding":"NR5A2 connects ZGA to the first lineage segregation: Nr5a2 knockdown/knockout causes arrest at morula stage with impaired 4-8C gene activation; NR5A2 binds cis-regulatory elements enriched for B1 elements in both 2C and 8C embryos; NR5A2 is not required for global opening of 2C binding sites but is essential for opening 8C-specific sites; NR5A2 directly regulates key pluripotency genes (Nanog, Pou5f1/Oct4), primitive endoderm genes (Gata6), and trophectoderm genes (Tead4, Gata3) at the 8C stage.","method":"Nr5a2 knockdown and knockout in mouse embryos, genome-wide ChIP/CUT&RUN, ATAC-seq, transcriptome analysis","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with genome-wide chromatin binding and accessibility analysis in embryos","pmids":["37935903"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of human NR5A2 bound to a nucleosome reveals the conserved CTE (carboxy-terminal extension) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome, releasing entry-exit site DNA; mutational analysis showed NR5A2 D159 of the CTE is dispensable for free DNA binding but required for stable nucleosome association and persistent DNA unwrapping, establishing the mechanism of NR5A2 pioneer activity.","method":"Cryo-electron microscopy of NR5A2-nucleosome complex, site-directed mutagenesis (D159), nucleosome binding assays, DNA unwrapping assays","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with mutagenesis and functional binding assays defining pioneer mechanism","pmids":["38409506"],"is_preprint":false},{"year":2024,"finding":"NR5A2 acts as a bipotency activator in totipotent (2-8 cell) mouse embryos: NR5A2 binds and activates both early ICM and trophectoderm lineage genes at the 8-cell stage; upon trophoblast commitment, NR5A2 transitions from ICM to TE gene regulation; NR5A2 binding at 8C-specific sites controls key pluripotency and TE regulatory genes.","method":"Conditional Tfap2c and Nr5a2 depletion in mouse embryos, ChIP-seq in embryos at multiple developmental stages, transcriptomic analysis","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq across developmental stages with genetic loss-of-function in embryos","pmids":["38243114"],"is_preprint":false},{"year":2024,"finding":"Nr5a2-/- mouse embryos arrest at early morula stage (not two-cell stage): Nr5a2 plays a minor role in ZGA but is a master regulator at the 8-cell stage controlling expression of lineage-specifying transcription factors and genes involved in mitosis, telomere maintenance, and DNA repair; Nr5a2-deficient embryos show frequent mitotic failure and chromosome segregation defects.","method":"Nr5a2 conditional and constitutive knockout mouse models, single-embryo transcriptomics, immunofluorescence for mitotic markers","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models resolving prior conflicting data, with transcriptomic and cytological phenotype analysis","pmids":["39361745"],"is_preprint":false}],"current_model":"NR5A2 (LRH-1/FTZ-F1 family) is a monomeric orphan nuclear receptor whose CTE/Ftz-F1 box domain mediates both sequence-specific DNA binding and pioneer activity via nucleosome minor groove anchor competition; it acts as a master transcriptional regulator at distinct developmental stages—including zygotic genome activation, first lineage segregation, pancreatic organogenesis, and ovarian folliculogenesis—where it directly controls gene programs for pluripotency (activating Nanog, Oct4), steroidogenesis (Cyp11a1, Star, Scarb1), acinar differentiation (Ptf1a, Rbpjl), and inflammation resolution (PTGS2-PGE2-PTGER1 axis), while its transcriptional activity is modulated by LXXLL-motif cofactors (e.g., Ftz, Prox1), coactivators (NCOA3, p160/SRC), post-translational SUMOylation, phospholipid ligands (PIP3), and antagonism by inflammatory transcription factors (c-Jun, NF-κB)."},"narrative":{"mechanistic_narrative":"NR5A2 (LRH-1; FTZ-F1 family) is a monomeric orphan nuclear receptor that functions as a sequence-specific, pioneer transcription factor governing developmental gene programs from the earliest embryo through organogenesis [PMID:36423263, PMID:38409506, PMID:25063451]. Its DNA-binding region combines a zinc finger with a conserved C-terminal FTZ-F1/CTE box that confers monomeric recognition of the extended PyCAAGG-type motif and binds DNA without an obligate ligand [PMID:1448096, PMID:8668203, PMID:8164672]. Structural work established that the FTZ-F1 box folds into a helix packing against the DBD to enable long-range communication with the ligand-binding domain and full transcriptional and coactivator output [PMID:16289203], while cryo-EM of an NR5A2-nucleosome complex showed the CTE loop competes with the nucleosomal DNA minor-groove anchor to release entry-exit DNA, defining the structural basis of NR5A2 pioneer activity [PMID:38409506]. In the early embryo NR5A2 binds its motif within SINE B1/Alu elements at cis-regulatory regions, opens chromatin, and acts as a master regulator of zygotic genome activation and the first lineage segregation, directly controlling pluripotency genes (Nanog, Pou5f1/Oct4) and lineage factors (Gata6, Tead4, Gata3), with loss causing morula-stage arrest, mitotic failure, and segregation defects [PMID:36423263, PMID:37935903, PMID:39361745, PMID:38243114]; consistent with this it can replace Oct4 in somatic reprogramming and, with Esrrb, sustains naive ESC self-renewal by controlling Oct4/Sox2/Nanog binding [PMID:20096661, PMID:34397088]. In organogenesis NR5A2 drives pancreatic progenitor expansion and acinar differentiation through mutually reinforcing regulation with PTF1A and a network including MYC, GATA4, FOXA2, RBPJL and MIST1, and its loss destabilizes the acinar state and accelerates Kras-driven metaplasia and inflammation [PMID:25063451, PMID:23645620, PMID:29443959]. In the ovary NR5A2 controls steroidogenesis and luteal progesterone synthesis via cholesterol-transport genes (Scarb1, Ldlr, Star) and granulosa cell proliferation [PMID:24552399, PMID:17409375, PMID:29379893]. NR5A2 transcriptional output is modulated by LXXLL/homeodomain cofactors (Ftz, Prox1), p160/SRC and NCOA3 coactivators, SUMOylation, and phospholipid (PIP3) binding within its LBD, and is antagonized by the inflammatory transcription factors c-Jun/AP-1 and NF-κB [PMID:11592991, PMID:15143342, PMID:17015464, PMID:20096661, PMID:26416531, PMID:24570488, PMID:29443959].","teleology":[{"year":1992,"claim":"Defined how the receptor achieves sequence-specific DNA recognition, establishing that an FTZ-F1 family receptor reads its element as a monomer using a dedicated basic box plus zinc finger.","evidence":"Gel mobility shift competition with mutant peptides for Drosophila FTZ-F1","pmids":["1448096"],"confidence":"High","gaps":["Did not address mammalian ortholog function in vivo","No structural model of the FTZ-F1 box"]},{"year":1996,"claim":"Extended the family to mammals and showed the vertebrate receptor binds its element as a monomer without an obligate ligand and activates target promoters, with a C-terminal truncation acting dominant-negative.","evidence":"cDNA cloning, Kd measurement, and reporter assays with truncation mutants for rat FTF","pmids":["8668203"],"confidence":"High","gaps":["Endogenous ligand undefined","Physiological target genes beyond AFP not yet mapped"]},{"year":1998,"claim":"Established the human gene (NR5A2/hB1F) as an FTZ-F1-family orphan receptor with defined DNA binding, transactivation, chromosomal locus, and splice isoforms.","evidence":"Yeast one-hybrid, binding and transactivation reporter assays, RT-PCR, FISH","pmids":["9786908"],"confidence":"High","gaps":["Endogenous human target genes not yet defined","No in vivo function established"]},{"year":2001,"claim":"Resolved the cofactor logic of the receptor, showing homeodomain partners engage both the DBD and the AF-2 surface via LXXLL-like motifs, and that mammalian SF-1 can substitute functionally in flies.","evidence":"In vitro pulldowns, domain mapping, and in vivo genetic rescue in Drosophila","pmids":["11520662","11592991"],"confidence":"High","gaps":["Did not identify vertebrate equivalents of these cofactors at the time","Structural basis of AF-2 docking not resolved"]},{"year":2005,"claim":"Provided the structural basis for DBD-LBD functional communication, showing the FTZ-F1 box helix is required for transcriptional activity and coactivator enhancement even though it does not contact DNA.","evidence":"X-ray crystallography of the human LRH-1 DBD-DNA complex with mutagenesis and reporter/coactivator assays","pmids":["16289203"],"confidence":"High","gaps":["Did not address nucleosomal DNA engagement","Mechanism of long-range communication not fully defined"]},{"year":2006,"claim":"Established the in vivo requirement for NR5A2 in mammalian development, showing it acts in extraembryonic tissues for epiblast gastrulation.","evidence":"Knockout mice with tetraploid complementation and marker analysis","pmids":["17075876"],"confidence":"High","gaps":["Did not resolve preimplantation roles","Direct target genes at gastrulation not mapped"]},{"year":2007,"claim":"Linked NR5A2 dosage causally to luteal steroidogenesis, showing reduced progesterone underlies the fertility defect and is rescued by progesterone supplementation.","evidence":"Nr5a2 heterozygous mice with hormone measurement and pharmacological rescue","pmids":["17409375"],"confidence":"High","gaps":["Direct steroidogenic target genes not yet identified","Cell-autonomous requirement not separated from systemic effects"]},{"year":2010,"claim":"Connected NR5A2 to the pluripotency network, showing it can replace Oct4 in reprogramming, shares targets with Sox2/Klf4, activates Nanog, and is negatively regulated by SUMOylation.","evidence":"Reprogramming assays, sumoylation-site mutagenesis, and genome-wide ChIP-chip in mouse cells","pmids":["20096661"],"confidence":"High","gaps":["Did not establish requirement in normal embryo pluripotency at this stage","SUMO-target sites mapped only functionally"]},{"year":2013,"claim":"Defined NR5A2 as a guardian of pancreatic acinar identity whose loss promotes metaplasia, inflammation, and Kras-driven neoplasia, linking it to NF-κB/STAT3 signaling.","evidence":"Conditional and heterozygous knockout mice with pancreatitis and Kras models, pathway analysis (two concurrent studies)","pmids":["23645620","23598351"],"confidence":"High","gaps":["Direct target genes mediating acinar maintenance not yet mapped","Mechanism connecting NR5A2 loss to NF-κB/STAT3 hyperactivation unresolved"]},{"year":2014,"claim":"Established NR5A2 as a direct controller of pancreatic organogenesis through a mutually reinforcing regulatory network with PTF1A and other lineage factors.","evidence":"Conditional inactivation with genome-wide ChIP and co-binding analysis at shared regulatory regions","pmids":["25063451"],"confidence":"High","gaps":["Did not resolve pioneer versus settler binding mode in this context","Hierarchy of NR5A2 versus PTF1A initiation not fully ordered"]},{"year":2014,"claim":"Defined direct ovarian steroidogenic and ovulatory targets, linking NR5A2 to Pgr and cholesterol-transport genes (Scarb1, Ldlr, Star) required for progesterone synthesis and ovulation.","evidence":"Granulosa-specific conditional knockout with hormone and gene expression analysis","pmids":["24552399"],"confidence":"High","gaps":["Direct versus indirect regulation of Pgr not fully separated","Cofactor dependence in granulosa cells not addressed here"]},{"year":2014,"claim":"Showed inflammatory signaling antagonizes NR5A2 directly, with c-Jun and NF-κB physically interacting with NR5A2 to repress its steroidogenic target Cyp11a1.","evidence":"Reporter assays, protein interaction, dominant-negative experiments, and a mouse colitis model","pmids":["24570488"],"confidence":"High","gaps":["Structural basis of NR5A2 repression by c-Jun/NF-κB unknown","Generality across NR5A2 target loci not established"]},{"year":2015,"claim":"Identified a phospholipid ligand mode, showing PIP3 binds the NR5A2 LBD with its tails buried and head group surface-exposed, stabilizing the domain.","evidence":"X-ray crystallography of the LBD-PIP3 complex with affinity and thermal stability measurement","pmids":["26416531"],"confidence":"High","gaps":["Physiological relevance of PIP3 occupancy in vivo not demonstrated","Effect on coactivator recruitment not directly tested"]},{"year":2016,"claim":"Broadened the developmental remit of NR5A2 to neural stem cell fate, where it directs neurogenesis over astrogliogenesis through Ink4/Arf, Prox1, Notch1 and JAK/STAT.","evidence":"Gain- and loss-of-function in primary NSCs and mouse embryos with target/pathway analysis","pmids":["27447294"],"confidence":"High","gaps":["Direct versus indirect regulation of listed targets not fully separated","Upstream control of NR5A2 in neural lineages partly inferred"]},{"year":2017,"claim":"Extended NR5A2 function to immune regulation, showing it directly drives FASLG transcription to control T cell apoptosis and cytotoxicity.","evidence":"ChIP, promoter mutagenesis, pharmacological inhibition, and a mouse hepatitis model","pmids":["28406481"],"confidence":"High","gaps":["Cofactor requirements at FASLG not defined","Endogenous ligand controlling this activity unknown"]},{"year":2018,"claim":"Revealed a regulatory switch in which reduced NR5A2 relocates from differentiation to inflammatory gene promoters in an AP-1-dependent manner, mechanistically uniting differentiation and inflammation control.","evidence":"Transcriptomics, NR5A2 ChIP-seq, and conditional Jun knockout rescue in pancreas","pmids":["29443959"],"confidence":"High","gaps":["Molecular trigger for promoter relocation unresolved","Whether relocation reflects altered cofactor availability not defined"]},{"year":2019,"claim":"Established a cell-intrinsic requirement for NR5A2 in T cell maturation, proliferation, and antiviral CD8+ responses.","evidence":"T cell-specific conditional knockout with proliferation, immunization, and viral challenge assays","pmids":["31328159"],"confidence":"High","gaps":["Direct transcriptional targets in T cells not mapped here","Relationship to FASLG regulation not integrated"]},{"year":2022,"claim":"Defined a multi-step islet survival pathway, showing NR5A2 induces PTGS2/COX2 to raise PGE2 acting through PTGER1 to protect beta cells and drive proliferation.","evidence":"Beta cell-specific knockout with agonist treatment and pharmacological dissection of PTGS2/PTGER1","pmids":["35602948"],"confidence":"High","gaps":["Direct NR5A2 occupancy at Ptgs2 not shown","Translation of agonist effects to human islets not established"]},{"year":2022,"claim":"Identified NR5A2 as an essential pioneer factor for zygotic genome activation, binding its motif in SINE B1/Alu elements to open chromatin and bind nucleosomal DNA.","evidence":"Embryo knockout, ATAC-seq, ChIP/CUT&RUN, in vitro nucleosome binding, and chemical inhibition","pmids":["36423263"],"confidence":"High","gaps":["Exact arrest stage and extent of ZGA dependence later contested","Structural basis of nucleosome engagement not yet defined here"]},{"year":2024,"claim":"Reconciled embryonic phenotypes and clarified NR5A2 as primarily an 8-cell/morula-stage master regulator of lineage factors, mitosis, telomere maintenance and DNA repair, with loss causing chromosome segregation defects.","evidence":"Multiple knockout models with single-embryo transcriptomics and mitotic immunofluorescence, plus ChIP-seq across stages defining bipotency activation of ICM and TE genes","pmids":["39361745","37935903","38243114"],"confidence":"High","gaps":["Mechanism linking NR5A2 to mitotic/DNA-repair gene control unresolved","How NR5A2 transitions from ICM to TE regulation not fully defined"]},{"year":2024,"claim":"Provided the structural mechanism of NR5A2 pioneer activity, showing the CTE loop competes with a nucleosomal minor-groove DNA anchor to release entry-exit DNA, with D159 required for stable nucleosome engagement.","evidence":"Cryo-EM of the NR5A2-nucleosome complex with D159 mutagenesis and DNA unwrapping assays","pmids":["38409506"],"confidence":"High","gaps":["Does not define how cofactors stabilize the unwrapped state in cells","Sequence determinants of nucleosomal site selection not fully resolved"]},{"year":null,"claim":"The endogenous physiological ligand that tunes NR5A2 activity across these contexts, and how a single pioneer receptor is directed to context-specific gene programs, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No defined endogenous ligand beyond in vitro PIP3 binding","Determinants of context-specific target selection unknown","Mechanism coupling chromatin opening to downstream coactivator recruitment in vivo not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,4,5,17,43,45]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,11,29,36,43]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[31]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[45]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[17,43,36]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[45,43]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,29,36,43]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[43,44,45]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[29,33,32,47]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[28,39]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[35,37,30]}],"complexes":[],"partners":["PTF1A","ESRRB","NCOA3","JUN","PROX1","HNF1","FTZ"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00482","full_name":"Nuclear receptor subfamily 5 group A member 2","aliases":["Alpha-1-fetoprotein transcription factor","B1-binding factor","hB1F","CYP7A promoter-binding factor","Hepatocytic transcription factor","Liver receptor homolog 1","LRH-1"],"length_aa":541,"mass_kda":61.3,"function":"Orphan nuclear receptor that binds DNA as a monomer to the 5'-TCAAGGCCA-3' sequence and controls expression of target genes: regulates key biological processes, such as early embryonic development, cholesterol and bile acid synthesis pathways, as well as liver and pancreas morphogenesis (PubMed:16289203, PubMed:18410128, PubMed:21614002, PubMed:32433991, PubMed:38409506, PubMed:9786908). Ligand-binding causes conformational change which causes recruitment of coactivators, promoting target gene activation (PubMed:21614002). The specific ligand is unknown, but specific phospholipids, such as phosphatidylethanolamine, phosphatidylserine, dilauroyl phosphatidylcholine and diundecanoyl phosphatidylcholine can act as ligand in vitro (PubMed:15707893, PubMed:15723037, PubMed:15897460, PubMed:21614002, PubMed:22504882, PubMed:23737522, PubMed:26416531, PubMed:26553876). Acts as a pioneer transcription factor, which unwraps target DNA from histones and elicits local opening of closed chromatin (PubMed:38409506). Plays a central role during preimplantation stages of embryonic development (By similarity). Plays a minor role in zygotic genome activation (ZGA) by regulating a small set of two-cell stage genes (By similarity). Plays a major role in morula development (2-16 cells embryos) by acting as a master regulator at the 8-cell stage, controlling expression of lineage-specifying transcription factors and genes involved in mitosis, telomere maintenance and DNA repair (By similarity). Zygotic NR5A2 binds to both closed and open chromatin with other transcription factors, often at SINE B1/Alu repeats DNA elements, promoting chromatin accessibility at nearby regulatory regions (By similarity). Also involved in the epiblast stage of development and embryonic stem cell pluripotency, by promoting expression of POU5F1/OCT4 (PubMed:27984042). Regulates other processes later in development, such as formation of connective tissue in lower jaw and middle ear, neural stem cell differentiation, ovarian follicle development and Sertoli cell differentiation (By similarity). Involved in exocrine pancreas development and acinar cell differentiation (By similarity). Acts as an essential transcriptional regulator of lipid metabolism (PubMed:20159957). Key regulator of cholesterol 7-alpha-hydroxylase gene (CYP7A) expression in liver (PubMed:10359768). Also acts as a negative regulator of inflammation in different organs, such as, liver and pancreas (PubMed:20159957). Protects against intestinal inflammation via its ability to regulate glucocorticoid production (By similarity). Plays an anti-inflammatory role during the hepatic acute phase response by acting as a corepressor: inhibits the hepatic acute phase response by preventing dissociation of the N-Cor corepressor complex (PubMed:20159957). Acts as a regulator of immunity by promoting lymphocyte T-cell development, proliferation and effector functions (By similarity). Also involved in resolution of endoplasmic reticulum stress in the liver (By similarity) In constrast to isoform 1 and isoform 2, does not induce cholesterol 7-alpha-hydroxylase gene (CYP7A) promoter activity (Microbial infection) Plays a crucial role for hepatitis B virus gene transcription and DNA replication. Mechanistically, synergistically cooperates with HNF1A to up-regulate the activity of one of the critical cis-elements in the hepatitis B virus genome enhancer II (ENII)","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/O00482/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NR5A2","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/NR5A2","total_profiled":1310},"omim":[{"mim_id":"616031","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 141; CCDC141","url":"https://www.omim.org/entry/616031"},{"mim_id":"614826","title":"NYSTAGMUS 7, CONGENITAL, AUTOSOMAL DOMINANT; NYS7","url":"https://www.omim.org/entry/614826"},{"mim_id":"611371","title":"ZINC FINGER PROTEIN 653; ZNF653","url":"https://www.omim.org/entry/611371"},{"mim_id":"604630","title":"NUCLEAR RECEPTOR SUBFAMILY 0, GROUP B, MEMBER 2; NR0B2","url":"https://www.omim.org/entry/604630"},{"mim_id":"604453","title":"NUCLEAR RECEPTOR SUBFAMILY 5, GROUP A, MEMBER 2; NR5A2","url":"https://www.omim.org/entry/604453"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nuclear speckles","reliability":"Uncertain"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":16.8},{"tissue":"liver","ntpm":36.1},{"tissue":"pancreas","ntpm":57.7}],"url":"https://www.proteinatlas.org/search/NR5A2"},"hgnc":{"alias_symbol":["FTZ-F1beta","hB1F","LRH-1","FTZ-F1","hB1F-2","B1F2","LRH1"],"prev_symbol":["FTF"]},"alphafold":{"accession":"O00482","domains":[{"cath_id":"3.30.50.10","chopping":"94-160","consensus_level":"high","plddt":92.9494,"start":94,"end":160},{"cath_id":"1.10.565.10","chopping":"302-539","consensus_level":"high","plddt":92.5451,"start":302,"end":539}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00482","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00482-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00482-F1-predicted_aligned_error_v6.png","plddt_mean":72.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NR5A2","jax_strain_url":"https://www.jax.org/strain/search?query=NR5A2"},"sequence":{"accession":"O00482","fasta_url":"https://rest.uniprot.org/uniprotkb/O00482.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00482/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00482"}},"corpus_meta":[{"pmid":"20096661","id":"PMC_20096661","title":"The nuclear receptor Nr5a2 can replace Oct4 in the reprogramming of murine somatic cells to pluripotent cells.","date":"2010","source":"Cell stem cell","url":"https://pubmed.ncbi.nlm.nih.gov/20096661","citation_count":382,"is_preprint":false},{"pmid":"8563022","id":"PMC_8563022","title":"Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice.","date":"1995","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/8563022","citation_count":305,"is_preprint":false},{"pmid":"1709303","id":"PMC_1709303","title":"FTZ-F1, a steroid hormone receptor-like protein implicated in the activation of fushi tarazu.","date":"1991","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/1709303","citation_count":270,"is_preprint":false},{"pmid":"8668203","id":"PMC_8668203","title":"The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8668203","citation_count":216,"is_preprint":false},{"pmid":"10078197","id":"PMC_10078197","title":"The Drosophila beta FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone.","date":"1999","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/10078197","citation_count":195,"is_preprint":false},{"pmid":"1448096","id":"PMC_1448096","title":"A novel DNA-binding motif abuts the zinc finger domain of insect nuclear hormone receptor FTZ-F1 and mouse embryonal long terminal repeat-binding protein.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1448096","citation_count":177,"is_preprint":false},{"pmid":"9020364","id":"PMC_9020364","title":"The nuclear hormone receptor Ftz-F1 is a cofactor for the Drosophila homeodomain protein Ftz.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9020364","citation_count":166,"is_preprint":false},{"pmid":"9020363","id":"PMC_9020363","title":"The nuclear receptor homologue Ftz-F1 and the homeodomain protein Ftz are mutually dependent cofactors.","date":"1997","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/9020363","citation_count":161,"is_preprint":false},{"pmid":"16281973","id":"PMC_16281973","title":"Zebrafish sex determination and differentiation: involvement of FTZ-F1 genes.","date":"2005","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/16281973","citation_count":147,"is_preprint":false},{"pmid":"8096644","id":"PMC_8096644","title":"Potential role for a FTZ-F1 steroid receptor superfamily member in the control of Drosophila metamorphosis.","date":"1993","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8096644","citation_count":145,"is_preprint":false},{"pmid":"1545809","id":"PMC_1545809","title":"Embryonal long terminal repeat-binding protein is a murine homolog of FTZ-F1, a member of the steroid receptor superfamily.","date":"1992","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/1545809","citation_count":140,"is_preprint":false},{"pmid":"23645620","id":"PMC_23645620","title":"Nr5a2 maintains acinar cell differentiation and constrains oncogenic Kras-mediated pancreatic neoplastic initiation.","date":"2013","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/23645620","citation_count":123,"is_preprint":false},{"pmid":"36423263","id":"PMC_36423263","title":"Zygotic genome activation by the totipotency pioneer factor Nr5a2.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/36423263","citation_count":120,"is_preprint":false},{"pmid":"10772806","id":"PMC_10772806","title":"nhr-25, the Caenorhabditis elegans ortholog of ftz-f1, is required for epidermal and somatic gonad development.","date":"2000","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10772806","citation_count":115,"is_preprint":false},{"pmid":"29443959","id":"PMC_29443959","title":"Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/29443959","citation_count":109,"is_preprint":false},{"pmid":"7706291","id":"PMC_7706291","title":"An E box element is required for the expression of the ad4bp gene, a mammalian homologue of ftz-f1 gene, which is essential for adrenal and gonadal development.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7706291","citation_count":104,"is_preprint":false},{"pmid":"11108279","id":"PMC_11108279","title":"Expression and regulation of transcripts encoding two members of the NR5A nuclear receptor subfamily of orphan nuclear receptors, steroidogenic factor-1 and NR5A2, in equine ovarian cells during the ovulatory process.","date":"2000","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11108279","citation_count":102,"is_preprint":false},{"pmid":"27809310","id":"PMC_27809310","title":"Downregulation of microRNA-27b-3p enhances tamoxifen resistance in breast cancer by increasing NR5A2 and CREB1 expression.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27809310","citation_count":94,"is_preprint":false},{"pmid":"9786908","id":"PMC_9786908","title":"Cloning and characterization of a novel human hepatocyte transcription factor, hB1F, which binds and activates enhancer II of hepatitis B virus.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9786908","citation_count":92,"is_preprint":false},{"pmid":"17015464","id":"PMC_17015464","title":"The competence factor beta Ftz-F1 potentiates ecdysone receptor activity via recruiting a p160/SRC coactivator.","date":"2006","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17015464","citation_count":90,"is_preprint":false},{"pmid":"10375033","id":"PMC_10375033","title":"Medaka (Oryzias latipes) FTZ-F1 potentially regulates the transcription of P-450 aromatase in ovarian follicles: cDNA cloning and functional characterization.","date":"1999","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10375033","citation_count":87,"is_preprint":false},{"pmid":"7491115","id":"PMC_7491115","title":"Steroidogenic factor 1 is the essential transcript of the mouse Ftz-F1 gene.","date":"1995","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7491115","citation_count":85,"is_preprint":false},{"pmid":"10971653","id":"PMC_10971653","title":"The conserved nuclear receptor Ftz-F1 is required for embryogenesis, moulting and reproduction in Caenorhabditis elegans.","date":"2000","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/10971653","citation_count":83,"is_preprint":false},{"pmid":"23598351","id":"PMC_23598351","title":"Nr5a2 heterozygosity sensitises to, and cooperates with, inflammation in KRas(G12V)-driven pancreatic tumourigenesis.","date":"2013","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/23598351","citation_count":82,"is_preprint":false},{"pmid":"25063451","id":"PMC_25063451","title":"The nuclear hormone receptor family member NR5A2 controls aspects of multipotent progenitor cell formation and acinar differentiation during pancreatic organogenesis.","date":"2014","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/25063451","citation_count":77,"is_preprint":false},{"pmid":"9043065","id":"PMC_9043065","title":"Ftz-F1 is a cofactor in Ftz activation of the Drosophila engrailed gene.","date":"1997","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/9043065","citation_count":71,"is_preprint":false},{"pmid":"8887679","id":"PMC_8887679","title":"Regulation of the EDG84A gene by FTZ-F1 during metamorphosis in Drosophila melanogaster.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8887679","citation_count":70,"is_preprint":false},{"pmid":"21131955","id":"PMC_21131955","title":"ftz-f1 and Hr39 opposing roles on EcR expression during Drosophila mushroom body neuron remodeling.","date":"2010","source":"Nature neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/21131955","citation_count":63,"is_preprint":false},{"pmid":"21391689","id":"PMC_21391689","title":"Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2).","date":"2011","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21391689","citation_count":62,"is_preprint":false},{"pmid":"8139576","id":"PMC_8139576","title":"FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8139576","citation_count":60,"is_preprint":false},{"pmid":"26398940","id":"PMC_26398940","title":"Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy.","date":"2015","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/26398940","citation_count":59,"is_preprint":false},{"pmid":"25446391","id":"PMC_25446391","title":"Involvement of FTZ-F1 in the regulation of pupation in Leptinotarsa decemlineata (Say).","date":"2014","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/25446391","citation_count":59,"is_preprint":false},{"pmid":"8164672","id":"PMC_8164672","title":"The Drosophila nuclear receptors FTZ-F1 alpha and FTZ-F1 beta compete as monomers for binding to a site in the fushi tarazu gene.","date":"1994","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8164672","citation_count":59,"is_preprint":false},{"pmid":"24737860","id":"PMC_24737860","title":"Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution.","date":"2014","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/24737860","citation_count":57,"is_preprint":false},{"pmid":"24552399","id":"PMC_24552399","title":"The orphan nuclear receptor Nr5a2 is essential for luteinization in the female mouse ovary.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24552399","citation_count":56,"is_preprint":false},{"pmid":"15143342","id":"PMC_15143342","title":"Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue.","date":"2004","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/15143342","citation_count":55,"is_preprint":false},{"pmid":"2124348","id":"PMC_2124348","title":"Identification and purification of a Bombyx mori homologue of FTZ-F1.","date":"1990","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2124348","citation_count":54,"is_preprint":false},{"pmid":"9413997","id":"PMC_9413997","title":"Temporal regulation of the mid-prepupal gene FTZ-F1: DHR3 early late gene product is one of the plural positive regulators.","date":"1997","source":"Genes to cells : devoted to molecular & cellular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/9413997","citation_count":54,"is_preprint":false},{"pmid":"8382937","id":"PMC_8382937","title":"FTZ-F1 beta, a novel member of the Drosophila nuclear receptor family.","date":"1993","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/8382937","citation_count":53,"is_preprint":false},{"pmid":"23637637","id":"PMC_23637637","title":"Scavenger receptors mediate the role of SUMO and Ftz-f1 in Drosophila steroidogenesis.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23637637","citation_count":53,"is_preprint":false},{"pmid":"16289203","id":"PMC_16289203","title":"Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity.","date":"2005","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16289203","citation_count":52,"is_preprint":false},{"pmid":"9332374","id":"PMC_9332374","title":"Molecular cloning of chicken FTZ-F1-related orphan receptors.","date":"1997","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/9332374","citation_count":52,"is_preprint":false},{"pmid":"26416531","id":"PMC_26416531","title":"Structure of Liver Receptor Homolog-1 (NR5A2) with PIP3 hormone bound in the ligand binding pocket.","date":"2015","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/26416531","citation_count":51,"is_preprint":false},{"pmid":"37935903","id":"PMC_37935903","title":"NR5A2 connects zygotic genome activation to the first lineage segregation in totipotent embryos.","date":"2023","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37935903","citation_count":49,"is_preprint":false},{"pmid":"11520662","id":"PMC_11520662","title":"The nuclear receptor Ftz-F1 and homeodomain protein Ftz interact through evolutionarily conserved protein domains.","date":"2001","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11520662","citation_count":48,"is_preprint":false},{"pmid":"15725073","id":"PMC_15725073","title":"Gene duplication, gene loss and evolution of expression domains in the vertebrate nuclear receptor NR5A (Ftz-F1) family.","date":"2005","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15725073","citation_count":46,"is_preprint":false},{"pmid":"9178748","id":"PMC_9178748","title":"Teleost FTZ-F1 homolog and its splicing variant determine the expression of the salmon gonadotropin IIbeta subunit gene.","date":"1997","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9178748","citation_count":45,"is_preprint":false},{"pmid":"17075797","id":"PMC_17075797","title":"The mRNA expression of P450 aromatase, gonadotropin beta-subunits and FTZ-F1 in the orange-spotted grouper (Epinephelus Coioides) during 17alpha-methyltestosterone-induced precocious sex change.","date":"2007","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/17075797","citation_count":44,"is_preprint":false},{"pmid":"12423370","id":"PMC_12423370","title":"A functionally conserved member of the FTZ-F1 nuclear receptor family from Schistosoma mansoni.","date":"2002","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12423370","citation_count":42,"is_preprint":false},{"pmid":"17075876","id":"PMC_17075876","title":"Nuclear receptor NR5A2 is required for proper primitive streak morphogenesis.","date":"2006","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/17075876","citation_count":39,"is_preprint":false},{"pmid":"22249180","id":"PMC_22249180","title":"The Drosophila juvenile hormone receptor candidates methoprene-tolerant (MET) and germ cell-expressed (GCE) utilize a conserved LIXXL motif to bind the FTZ-F1 nuclear receptor.","date":"2012","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/22249180","citation_count":39,"is_preprint":false},{"pmid":"14728801","id":"PMC_14728801","title":"LRH-1/hB1F and HNF1 synergistically up-regulate hepatitis B virus gene transcription and DNA replication.","date":"2003","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/14728801","citation_count":38,"is_preprint":false},{"pmid":"22019437","id":"PMC_22019437","title":"FTZ-F1 and FOXL2 up-regulate catfish brain aromatase gene transcription by specific binding to the promoter motifs.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22019437","citation_count":37,"is_preprint":false},{"pmid":"9644266","id":"PMC_9644266","title":"Adrenocortical and gonadal expression of the mammalian Ftz-F1 gene encoding Ad4BP/SF-1 is independent of pituitary control.","date":"1998","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9644266","citation_count":37,"is_preprint":false},{"pmid":"29379893","id":"PMC_29379893","title":"The Orphan Nuclear Receptor Liver Homolog Receptor-1 (Nr5a2) Regulates Ovarian Granulosa Cell Proliferation.","date":"2017","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/29379893","citation_count":36,"is_preprint":false},{"pmid":"38243114","id":"PMC_38243114","title":"Lineage regulators TFAP2C and NR5A2 function as bipotency activators in totipotent embryos.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38243114","citation_count":35,"is_preprint":false},{"pmid":"24611773","id":"PMC_24611773","title":"Function of the nuclear receptor FTZ-F1 during the pupal stage in Drosophila melanogaster.","date":"2014","source":"Development, growth & differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/24611773","citation_count":35,"is_preprint":false},{"pmid":"8626518","id":"PMC_8626518","title":"Autoregulatory loop in the regulation of the mammalian ftz-f1 gene.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8626518","citation_count":35,"is_preprint":false},{"pmid":"30471186","id":"PMC_30471186","title":"Transcription factor FTZ-F1 and cis-acting elements mediate expression of CYP6BG1 conferring resistance to chlorantraniliprole in Plutella xylostella.","date":"2019","source":"Pest management science","url":"https://pubmed.ncbi.nlm.nih.gov/30471186","citation_count":34,"is_preprint":false},{"pmid":"16621513","id":"PMC_16621513","title":"Transcriptional regulation of the rainbow trout CYP19a gene by FTZ-F1 homologue.","date":"2006","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/16621513","citation_count":34,"is_preprint":false},{"pmid":"27447294","id":"PMC_27447294","title":"Nuclear receptor NR5A2 controls neural stem cell fate decisions during development.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27447294","citation_count":33,"is_preprint":false},{"pmid":"27474396","id":"PMC_27474396","title":"Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development.","date":"2016","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/27474396","citation_count":33,"is_preprint":false},{"pmid":"24570488","id":"PMC_24570488","title":"Tumor necrosis factor suppresses NR5A2 activity and intestinal glucocorticoid synthesis to sustain chronic colitis.","date":"2014","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/24570488","citation_count":33,"is_preprint":false},{"pmid":"27996162","id":"PMC_27996162","title":"Effect of NR5A2 inhibition on pancreatic cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) markers.","date":"2017","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27996162","citation_count":32,"is_preprint":false},{"pmid":"33078511","id":"PMC_33078511","title":"Dissecting the roles of FTZ-F1 in larval molting and pupation, and the sublethal effects of methoxyfenozide on Helicoverpa armigera.","date":"2020","source":"Pest management science","url":"https://pubmed.ncbi.nlm.nih.gov/33078511","citation_count":32,"is_preprint":false},{"pmid":"17409375","id":"PMC_17409375","title":"Impaired progesterone production in Nr5a2+/- mice leads to a reduction in female reproductive function.","date":"2007","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/17409375","citation_count":32,"is_preprint":false},{"pmid":"11595170","id":"PMC_11595170","title":"Characterization of the genomic structure and tissue-specific promoter of the human nuclear receptor NR5A2 (hB1F) gene.","date":"2001","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11595170","citation_count":31,"is_preprint":false},{"pmid":"30740909","id":"PMC_30740909","title":"Nr5a2 promotes cancer stem cell properties and tumorigenesis in nonsmall cell lung cancer by regulating Nanog.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30740909","citation_count":31,"is_preprint":false},{"pmid":"34397088","id":"PMC_34397088","title":"The combined action of Esrrb and Nr5a2 is essential for murine naïve pluripotency.","date":"2021","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34397088","citation_count":31,"is_preprint":false},{"pmid":"10816440","id":"PMC_10816440","title":"Zebrafish ftz-f1 gene has two promoters, is alternatively spliced, and is expressed in digestive organs.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10816440","citation_count":30,"is_preprint":false},{"pmid":"30270498","id":"PMC_30270498","title":"Hormonal control and target genes of ftz-f1 expression in the honeybee Apis mellifera: a positive loop linking juvenile hormone, ftz-f1, and vitellogenin.","date":"2018","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/30270498","citation_count":29,"is_preprint":false},{"pmid":"32536370","id":"PMC_32536370","title":"NR5A2 synergizes with NCOA3 to induce breast cancer resistance to BET inhibitor by upregulating NRF2 to attenuate ferroptosis.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32536370","citation_count":29,"is_preprint":false},{"pmid":"10806365","id":"PMC_10806365","title":"Two isoforms of FTZ-F1 messenger RNA: molecular cloning and their expression in the frog testis.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/10806365","citation_count":28,"is_preprint":false},{"pmid":"32338596","id":"PMC_32338596","title":"Nuclear receptor Ftz-f1 promotes follicle maturation and ovulation partly via bHLH/PAS transcription factor Sim.","date":"2020","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/32338596","citation_count":27,"is_preprint":false},{"pmid":"11178880","id":"PMC_11178880","title":"Developmental expression patterns of FTZ-F1 homologues in zebrafish (Danio rerio).","date":"2001","source":"General and comparative endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11178880","citation_count":27,"is_preprint":false},{"pmid":"33441767","id":"PMC_33441767","title":"A role for orphan nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in primordial follicle activation.","date":"2021","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33441767","citation_count":26,"is_preprint":false},{"pmid":"28074850","id":"PMC_28074850","title":"Juvenile hormone biosynthesis in adult Blattella germanica requires nuclear receptors Seven-up and FTZ-F1.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28074850","citation_count":26,"is_preprint":false},{"pmid":"32111818","id":"PMC_32111818","title":"Pharmacological LRH-1/Nr5a2 inhibition limits pro-inflammatory cytokine production in macrophages and associated experimental hepatitis.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32111818","citation_count":25,"is_preprint":false},{"pmid":"11592991","id":"PMC_11592991","title":"Segmentation gene product Fushi tarazu is an LXXLL motif-dependent coactivator for orphan receptor FTZ-F1.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11592991","citation_count":25,"is_preprint":false},{"pmid":"7476970","id":"PMC_7476970","title":"A naturally occurring short variant of the FTZ-F1-related nuclear orphan receptor xFF1rA and interactions between domains of xFF1rA.","date":"1995","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7476970","citation_count":25,"is_preprint":false},{"pmid":"31328159","id":"PMC_31328159","title":"The orphan nuclear receptor LRH-1/NR5a2 critically regulates T cell functions.","date":"2019","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/31328159","citation_count":24,"is_preprint":false},{"pmid":"34643922","id":"PMC_34643922","title":"Nuclear receptor subfamily 5 group A member 2 (NR5A2): role in health and diseases.","date":"2021","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/34643922","citation_count":22,"is_preprint":false},{"pmid":"38409506","id":"PMC_38409506","title":"Nucleosome-bound NR5A2 structure reveals pioneer factor mechanism by DNA minor groove anchor competition.","date":"2024","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38409506","citation_count":22,"is_preprint":false},{"pmid":"33850096","id":"PMC_33850096","title":"NR5A2 transcriptional activation by BRD4 promotes pancreatic cancer progression by upregulating GDF15.","date":"2021","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/33850096","citation_count":22,"is_preprint":false},{"pmid":"30618850","id":"PMC_30618850","title":"Genome-Wide Screening and Functional Analysis Reveal That the Specific microRNA nlu-miR-173 Regulates Molting by Targeting Ftz-F1 in Nilaparvata lugens.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30618850","citation_count":22,"is_preprint":false},{"pmid":"28406481","id":"PMC_28406481","title":"Liver receptor homolog-1 (NR5a2) regulates CD95/Fas ligand transcription and associated T-cell effector functions.","date":"2017","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/28406481","citation_count":21,"is_preprint":false},{"pmid":"24261442","id":"PMC_24261442","title":"The evolving role of the orphan nuclear receptor ftz-f1, a pair-rule segmentation gene.","date":"2013","source":"Evolution & development","url":"https://pubmed.ncbi.nlm.nih.gov/24261442","citation_count":21,"is_preprint":false},{"pmid":"32931651","id":"PMC_32931651","title":"Nuclear-mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog-1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer.","date":"2020","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/32931651","citation_count":20,"is_preprint":false},{"pmid":"35602948","id":"PMC_35602948","title":"NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway contributing to pancreatic islet survival and function.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/35602948","citation_count":20,"is_preprint":false},{"pmid":"31114234","id":"PMC_31114234","title":"Nr5a2 promotes tumor growth and metastasis of gastric cancer AGS cells by Wnt/beta-catenin signaling.","date":"2019","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/31114234","citation_count":20,"is_preprint":false},{"pmid":"15961510","id":"PMC_15961510","title":"A FTZ-F1-containing yeast artificial chromosome recapitulates expression of steroidogenic factor 1 in vivo.","date":"2005","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/15961510","citation_count":20,"is_preprint":false},{"pmid":"16870276","id":"PMC_16870276","title":"Identification and characterization of a novel fushi tarazu factor 1 (FTZ-F1) nuclear receptor in Schistosoma mansoni.","date":"2006","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/16870276","citation_count":20,"is_preprint":false},{"pmid":"23536856","id":"PMC_23536856","title":"NR5A2 regulates Lhb and Fshb transcription in gonadotrope-like cells in vitro, but is dispensable for gonadotropin synthesis and fertility in vivo.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23536856","citation_count":20,"is_preprint":false},{"pmid":"24632207","id":"PMC_24632207","title":"Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells.","date":"2014","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/24632207","citation_count":19,"is_preprint":false},{"pmid":"33054862","id":"PMC_33054862","title":"Transcription factor FTZ-F1 regulates mosquito cuticular protein CPLCG5 conferring resistance to pyrethroids in Culex pipiens pallens.","date":"2020","source":"Parasites & vectors","url":"https://pubmed.ncbi.nlm.nih.gov/33054862","citation_count":19,"is_preprint":false},{"pmid":"39361745","id":"PMC_39361745","title":"Nr5a2 is dispensable for zygotic genome activation but essential for morula development.","date":"2024","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/39361745","citation_count":18,"is_preprint":false},{"pmid":"16996052","id":"PMC_16996052","title":"Computational identification of Ftz/Ftz-F1 downstream target genes.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/16996052","citation_count":18,"is_preprint":false},{"pmid":"9722168","id":"PMC_9722168","title":"Candidate genes in complete and partial XY sex reversal: mutation analysis of SRY, SRY-related genes and FTZ-F1.","date":"1998","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9722168","citation_count":18,"is_preprint":false},{"pmid":"24459144","id":"PMC_24459144","title":"Retinoic acid receptor γ (Rarg) and nuclear receptor subfamily 5, group A, member 2 (Nr5a2) promote conversion of fibroblasts to functional neurons.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24459144","citation_count":18,"is_preprint":false},{"pmid":"28520915","id":"PMC_28520915","title":"Ovary-specific depletion of the nuclear receptor Nr5a2 compromises expansion of the cumulus oophorus but not fertilization by intracytoplasmic sperm injection.","date":"2017","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/28520915","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49724,"output_tokens":11508,"usd":0.160896,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22795,"output_tokens":6202,"usd":0.134513,"stage2_stop_reason":"end_turn"},"total_usd":0.295409,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"FTZ-F1 is a member of the nuclear hormone receptor superfamily that binds the zebra element of the fushi tarazu (ftz) gene and activates ftz transcription, particularly in stripes 1, 2, 3, and 6 of the Drosophila embryo.\",\n      \"method\": \"cDNA cloning by recognition site screening, immunological cross-reaction, peptide sequence analysis, DNA binding assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cloning and biochemical identification, replicated across multiple subsequent studies\",\n      \"pmids\": [\"1709303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"FTZ-F1 contains a conserved 30-amino-acid basic region (the FTZ-F1 box) C-terminal to the zinc finger motif; gel mobility shift competition assays showed the FTZ-F1 box governs recognition of the first three bases of the binding sequence (5'-PyCAAGGPyCPu-3') while the zinc finger recognizes the remainder, and FTZ-F1 binds DNA as a monomer.\",\n      \"method\": \"Gel mobility shift competition with mutant peptides, gel mobility shift matrix competition assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical mutagenesis with multiple orthogonal binding assays, conserved across species (fruit fly, silkworm, mouse)\",\n      \"pmids\": [\"1448096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"Mouse ELP (embryonal long terminal repeat-binding protein) is a homolog of Drosophila FTZ-F1, both sharing conserved DNA-binding and putative ligand-binding domains and recognizing the same non-repeat DNA sequence element, functioning in undifferentiated embryonal carcinoma cells.\",\n      \"method\": \"cDNA cloning, sequence analysis, DNA binding assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sequence and binding analysis across two species, single lab\",\n      \"pmids\": [\"1545809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"A developmental isoform of FTZ-F1 (beta FTZ-F1) is expressed from a mid-prepupal chromosome puff (75CD) in Drosophila and binds over 150 chromosomal targets including late prepupal puffs, implicating it as a regulator of insect metamorphosis downstream of ecdysone.\",\n      \"method\": \"cDNA cloning, indirect immunofluorescent staining on polytene chromosomes\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct chromosomal binding demonstrated by immunofluorescence, single lab\",\n      \"pmids\": [\"8096644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"FTZ-F1 alpha and FTZ-F1 beta both bind as monomers to the 9-bp F1RE in the ftz zebra element with similar affinities and sequence specificities, and both contribute to net transcriptional activity; they do not form heterodimers with each other.\",\n      \"method\": \"In vitro DNase I footprinting, gel mobility shift with recombinant proteins and N-terminally truncated receptors, cotransfection reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with recombinant proteins, footprinting, and functional cotransfection, multiple orthogonal methods\",\n      \"pmids\": [\"8164672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Rat FTF (fetoprotein transcription factor, ortholog of NR5A2) is an orphan nuclear receptor of the FTZ-F1 family that recognizes the DNA sequence 5'-TCAAGGTCA-3' and activates the alpha1-fetoprotein (AFP) promoter; it binds DNA as a monomer without requiring a specific ligand, and C-terminus-truncated FTF exerts dominant negative effects.\",\n      \"method\": \"cDNA cloning, DNA binding assays, transient transfection with deletion/truncation mutants, Kd measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro binding quantification, dominant-negative mutagenesis, and transcriptional activation assays in a single paper\",\n      \"pmids\": [\"8668203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The mammalian ftz-f1 gene (encoding Ad4BP/SF-1) contains an intronic Ad4 site to which Ad4BP itself binds, creating an autoregulatory loop that maintains high expression specifically in steroidogenic tissues; DNase I hypersensitivity showed this chromatin region is 'open' in adrenal and Y-1 cells but 'closed' in liver.\",\n      \"method\": \"Gel mobility shift assay, DNase I footprinting, DNase I hypersensitivity, site-directed mutagenesis, transient transfection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods including mutagenesis, chromatin analysis, and functional reporter assays\",\n      \"pmids\": [\"8626518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"FTZ-F1 directly regulates the pupal cuticle gene EDG84A in Drosophila: heat-induction of FTZ-F1 causes premature EDG84A expression; mutation of the FTZ-F1 binding site in the EDG84A promoter abolishes reporter expression in transgenic flies.\",\n      \"method\": \"Heat-shock induction of FTZ-F1 transgene, lacZ reporter transgenics, base substitution mutagenesis of FTZ-F1 binding site\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vivo gain-of-function and promoter mutagenesis in transgenic Drosophila\",\n      \"pmids\": [\"8887679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Ftz-F1 (nuclear hormone receptor) and the homeodomain protein Ftz are present in a complex in Drosophila embryos; Ftz-F1 facilitates binding of Ftz to DNA and allows Ftz to interact with weak-affinity sites; embryos lacking Ftz-F1 display ftz-like pair-rule defects and fail to activate Ftz target genes despite Ftz being expressed.\",\n      \"method\": \"Co-immunoprecipitation from Drosophila embryo extracts, in vitro DNA binding facilitation assays, genetic analysis of ftz-f1 mutants\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal biochemical interaction plus in vivo genetic validation, two independent concurrent papers (PMID 9020364, 9020363)\",\n      \"pmids\": [\"9020364\", \"9020363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Ftz and Ftz-F1 interact directly and specifically in vitro and in vivo through a conserved domain in Ftz; Ftz-F1 is an obligatory maternal cofactor for Ftz function in Drosophila segmentation.\",\n      \"method\": \"In vitro binding assays, in vivo genetic rescue experiments, domain mapping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct protein interaction established in vitro and validated in vivo, replicated concurrently by two independent labs\",\n      \"pmids\": [\"9020363\", \"9020364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Ftz-F1 and Ftz cooperate to activate the engrailed gene via adjacent conserved binding sites in an engrailed enhancer; Ftz-F1 and Ftz bind these sites with 4- to 8-fold cooperativity, suggesting direct protein-protein contact.\",\n      \"method\": \"DNase I footprinting, gel mobility shift assay, transgenic reporter analysis, genetic epistasis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cooperative DNA binding demonstrated biochemically, validated by in vivo reporter and genetics\",\n      \"pmids\": [\"9043065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Human NR5A2 (hB1F) is an orphan nuclear receptor of the FTZ-F1 family that specifically binds the B1 region of hepatitis B virus enhancer II (ENII) and trans-activates ENII; mapped to chromosome 1q31-32.1; a splice isoform hB1F-2 with an extra 46 amino acids in the A/B region was identified.\",\n      \"method\": \"Yeast one-hybrid screening, DNA binding assays, transactivation reporter assays, RT-PCR, FISH\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding and transactivation demonstrated with multiple assays, foundational characterization of human NR5A2\",\n      \"pmids\": [\"9786908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Beta FTZ-F1 (Drosophila ortholog of NR5A2) functions as a competence factor for stage-specific responses to ecdysone during metamorphosis; beta FTZ-F1 mutants cannot respond properly to the prepupal ecdysone pulse and the ecdysone-triggered genetic hierarchy is severely attenuated, though ecdysone receptor expression is unaffected.\",\n      \"method\": \"Genetic analysis of beta FTZ-F1 loss-of-function mutants, molecular analysis of downstream ecdysone target gene expression\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined molecular phenotype, epistasis placing beta FTZ-F1 upstream of ecdysone-response hierarchy\",\n      \"pmids\": [\"10078197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The Ftz-F1/Ftz interaction involves two surfaces: the Ftz-F1 DNA-binding domain interacts strongly with Ftz and facilitates Ftz binding to target DNA; the AF-2 domain of Ftz-F1 interacts with an LRALL sequence in Ftz (resembling nuclear receptor coactivator LXXLL motifs); murine SF-1 functionally substitutes for Drosophila Ftz-F1 in vivo, demonstrating evolutionary conservation.\",\n      \"method\": \"In vitro pulldown/binding assays, domain mapping with truncation mutants, in vivo genetic rescue experiments in Drosophila\",\n      \"journal\": \"Mechanisms of development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of interaction domains plus in vivo genetic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"11520662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Ftz acts as an LXXLL motif-dependent coactivator for the orphan receptor FTZ-F1: the Ftz LXXLL motif and FTZ-F1 AF-2 core/LBD are required for interaction as shown by mammalian two-hybrid assays; this interaction is required for FTZ-F1 activation of target genes in Drosophila embryos and for the cuticle phenotype.\",\n      \"method\": \"Mammalian one- and two-hybrid assays, LXXLL motif mutagenesis, transgenic fly analysis of target gene expression and cuticle phenotype\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — domain mutagenesis with in vivo validation in transgenic Drosophila\",\n      \"pmids\": [\"11592991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human LRH-1/hB1F (NR5A2) and HNF1 directly interact in vitro and synergize to activate hepatitis B virus enhancer II (ENII) and initiate viral gene transcription and DNA replication even in non-hepatic cells; specific activation domains in both proteins contribute to this synergism.\",\n      \"method\": \"In vitro protein interaction assays, cotransfection reporter assays in non-hepatic cells, domain mapping\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein interaction and functional synergism demonstrated, single lab\",\n      \"pmids\": [\"14728801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The homeodomain protein Prox1 functions as a co-repressor for human LRH-1 (NR5A2), demonstrating functional conservation of Drosophila Ftz/Ftz-F1 homeodomain–nuclear receptor interaction in vertebrates; Prox1 represses LRH-1 transcriptional activity in the enterohepatic system.\",\n      \"method\": \"Protein interaction assays, cotransfection reporter assays, characterization in liver cell lines\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and functional repression shown, single lab, limited orthogonal methods described in abstract\",\n      \"pmids\": [\"15143342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Crystal structure of the human LRH-1 (NR5A2) DBD-DNA complex at 2.2 Å shows the Ftz-F1 box folds into a novel helix that packs against the DBD but does not directly contact DNA; mutations disrupting Ftz-F1 helix positioning do not eliminate DNA binding but significantly reduce transcriptional activity and eliminate GRIP1 coactivator enhancement, revealing long-range DBD→LBD functional communication.\",\n      \"method\": \"X-ray crystallography, site-directed mutagenesis, transcriptional reporter assays, coactivator recruitment assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and functional assays in one study\",\n      \"pmids\": [\"16289203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Beta FTZ-F1 potentiates ecdysone receptor (EcR) activity by recruiting a p160/SRC coactivator (FISC) through direct protein-protein interaction; this interaction dramatically increases FISC recruitment to the functional ecdysone receptor in a 20E-dependent manner, enhances local histone H4 acetylation, and drives stage-specific 20E effector gene expression during mosquito reproduction.\",\n      \"method\": \"Protein-protein interaction assays, ChIP, histone acetylation analysis, gene expression analysis in vivo\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction plus ChIP plus histone modification analysis, multiple orthogonal methods\",\n      \"pmids\": [\"17015464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"NR5A2 knockout mice display embryonic lethality around gastrulation: NR5A2-/- embryos show primitive streak formation failure and inability to generate embryonic or extraembryonic mesoderm; tetraploid complementation showed NR5A2 is required in extraembryonic tissues for epiblast gastrulation.\",\n      \"method\": \"Targeted gene disruption (knockout mice), morphological analysis, marker gene expression, tetraploid complementation aggregation experiments\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional rescue experiment (tetraploid complementation) plus full phenotypic characterization\",\n      \"pmids\": [\"17075876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nr5a2 heterozygous female mice show reduced fertility arising from decreased circulating progesterone and impaired luteal function, without defects in follicular development, ovulation, or estrogen production; exogenous progesterone supplementation rescues reproductive ability, establishing Nr5a2 as an in vivo regulator of luteal steroidogenesis.\",\n      \"method\": \"Nr5a2+/- mice, hormone measurements, progesterone rescue experiment, reproductive outcome assessment\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with pharmacological rescue, direct causal link between Nr5a2 dose and progesterone production\",\n      \"pmids\": [\"17409375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Nr5a2 (LRH-1) can replace Oct4 in the reprogramming of mouse somatic cells to iPSCs; sumoylation mutants of Nr5a2 with enhanced transcriptional activity further increase reprogramming efficiency; genome-wide location analysis shows Nr5a2 shares common gene targets with Sox2 and Klf4; Nr5a2 activates Nanog as part of its reprogramming mechanism.\",\n      \"method\": \"Retroviral reprogramming assay, sumoylation site mutagenesis, genome-wide ChIP-chip location analysis, Nanog reporter and expression analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional replacement assay, genome-wide binding analysis, and mechanistic follow-up via Nanog activation\",\n      \"pmids\": [\"20096661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Small molecule agonists of LRH-1/NR5A2 can bind its ligand-binding domain; crystal structure of LRH-1 LBD bound to a synthetic agonist defined the binding pocket and guided structure-activity relationship studies yielding LRH-1-selective (RJW101) and dual LRH-1/SF-1 agonists (RJW100) with activity at endogenous target genes in human cell lines.\",\n      \"method\": \"X-ray crystallography of LBD-ligand complex, peptide recruitment assay, structure-activity relationship medicinal chemistry, endogenous gene expression assays\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation in human cells, multiple agonist series characterized\",\n      \"pmids\": [\"21391689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila FTZ-F1 interacts with juvenile hormone receptor candidates MET and GCE in a JH-dependent manner via AF-2/LXXLL (LIXXL) interaction; removal of FTZ-F1 helix 12 (AF2) severely reduces interaction; the interaction relies on hydrophobic contacts including a unique interaction with helix 4, without requiring canonical charge clamp residues.\",\n      \"method\": \"Insect two-hybrid assays, homology modeling, docking simulations, domain deletion analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid assays with domain analysis, supported by modeling, single lab\",\n      \"pmids\": [\"22249180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nr5a2 conditional deletion in the pancreas leads to destabilization of mature acinar differentiation, acinar-to-ductal metaplasia, loss of regenerative capacity after pancreatitis, and dramatically accelerates Kras-driven acinar-to-ductal metaplasia and PDA precursor development.\",\n      \"method\": \"Conditional knockout mice (PdxCre-late; Nr5a2 c/c), caerulein pancreatitis model, histology, marker analysis\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout with multiple disease models, replicated findings across two concurrent labs (PMID 23645620, 23598351)\",\n      \"pmids\": [\"23645620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Nr5a2 haploinsufficiency sensitizes the pancreas to caerulein-induced damage with increased acino-ductal metaplasia, impaired recovery, myeloid cell infiltration, and proinflammatory cytokine expression with hyperactivation of NF-κB and STAT3; a single acute pancreatitis episode cooperates with Kras(G12V) to accelerate preneoplastic lesion development.\",\n      \"method\": \"Nr5a2+/- and conditional Nr5a2 epithelial-specific knockout mice, caerulein pancreatitis model, molecular pathway analysis (NF-κB, STAT3)\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model with molecular pathway analysis, replicated across two concurrent publications\",\n      \"pmids\": [\"23598351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Drosophila Ftz-f1 is SUMOylated in vitro and in vivo; SUMO levels regulate Ftz-f1 expression, and Ftz-f1 in turn drives expression of scavenger receptor Snmp1, which mediates lipid uptake in steroidogenic tissues for ecdysteroid biosynthesis.\",\n      \"method\": \"In vitro and in vivo SUMOylation assays, RNAi knockdown in Drosophila, lipid staining, hormone titer measurements, genetic epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo SUMOylation demonstrated with functional genetic epistasis, single lab\",\n      \"pmids\": [\"23637637\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LRH-1 (NR5A2) initiates an ER stress resolution pathway independent of canonical UPR: in response to ER stress, LRH-1 induces expression of kinase Plk3, which phosphorylates and activates transcription factor ATF2; hepatic Lrh-1-null mice cannot resolve ER stress, and restoring Plk3 rescues ER stress resolution in Lrh-1-null cells; LRH-1 agonist treatment increases ER stress resistance.\",\n      \"method\": \"Hepatic conditional Lrh-1 knockout mice, Plk3 knockout mice, viral rescue of Plk3, ATF2 manipulation, ER stress induction assays, LRH-1 agonist treatment\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (KO, rescue) defining a novel pathway with pharmacological validation\",\n      \"pmids\": [\"24737860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nr5a2 granulosa-specific depletion prevents ovulation (at least partly through downregulation of the progesterone receptor gene Pgr) and impairs luteal function with reduced progesterone synthesis due to defects in cholesterol transport (down-regulation of Scarb1, Ldlr, Star).\",\n      \"method\": \"Conditional knockout mice (Nr5a2-Cyp19-Cre), hormone measurements, gene expression analysis, pseudopregnancy test\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with mechanistic pathway analysis linking Nr5a2 to cholesterol transport genes and progesterone synthesis\",\n      \"pmids\": [\"24552399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NR5A2 is required during pancreatic organogenesis for expansion of nascent pancreatic epithelium, formation of multipotent progenitor cells, and acinar differentiation; NR5A2 directly controls expression and regulatory interactions with PTF1A, MYC, GATA4, FOXA2, RBPJL, and MIST1; Nr5a2 and Ptf1a establish mutually reinforcing regulatory interactions and bind shared regulatory regions of pancreatic genes.\",\n      \"method\": \"Conditional gene inactivation, genome-wide binding analysis (ChIP), expression analysis, co-binding analysis at shared regulatory regions\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO plus genome-wide ChIP establishing direct target relationships and co-regulatory interactions\",\n      \"pmids\": [\"25063451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TNF suppresses intestinal glucocorticoid synthesis by activating c-Jun and NF-κB, both of which physically interact with NR5A2 and repress Cyp11a1 reporter activity; dominant-negative JNK1 or IκB relieves repression; NR5A2 activity is thus antagonized by inflammatory signals to sustain chronic colitis.\",\n      \"method\": \"Reporter assays, protein interaction (c-Jun/NF-κB with NR5A2), dominant-negative experiments, mouse colitis model with TNF inhibitor rescue\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein-protein interaction with functional reporter assays and in vivo mouse model rescue\",\n      \"pmids\": [\"24570488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human LRH-1 (NR5A2) LBD bound by PIP3 (PI(3,4,5)P3) at high affinity; the hydrophobic PIP3 tails are buried inside the LBD ligand-binding pocket while the negatively charged PIP3 head group is presented on the receptor surface, similar to PIP3-SF-1 binding mode; PIP3 binding stabilizes the LRH-1 LBD.\",\n      \"method\": \"X-ray crystallography of LBD-PIP3 complex, binding affinity measurement, thermal stability assay\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation, extends prior SF-1 structural data to NR5A2\",\n      \"pmids\": [\"26416531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NR5A2 controls neural stem cell fate decisions: overexpression promotes neurogenesis and inhibits astrogliogenesis; loss-of-function delays neuronal differentiation; NR5A2 directly regulates the Ink4/Arf locus, Prox1, Notch1 and JAK/STAT signaling; upstream regulation of NR5A2 involves proneural genes, Notch1, and JAK/STAT pathways.\",\n      \"method\": \"Overexpression and shRNA knockdown in primary neural stem cells and mouse embryos in utero, target gene expression analysis, pathway analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss- and gain-of-function with multiple target pathway analyses, in vivo and in vitro validation\",\n      \"pmids\": [\"27447294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In zebrafish, nr5a2 (ortholog of mammalian NR5A2) is required for acinar cell differentiation of the exocrine pancreas and for hepatic progenitor outgrowth and differentiation; chemical inhibition of Nr5a2 during hepatopancreas progenitor specification disrupts exocrine pancreas formation and enhances liver size, indicating Nr5a2 regulates hepatic vs. pancreatic progenitor fate choice.\",\n      \"method\": \"Targeted genetic null mutant in zebrafish, chemical antagonist (Cpd3) temporal inhibition, marker gene analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null plus temporally controlled chemical inhibition dissecting iterative roles\",\n      \"pmids\": [\"27474396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Nr5a2 is essential for granulosa cell proliferation: conditional knockout reduces proliferation (assessed by BrdU, PCNA, FACS); downregulates cyclin transcripts (Ccnd1, Ccnd2, Ccne1, Ccne2, E2f1, E2f2); pharmacological inhibition by ML180 reverse agonist or β-catenin inhibition similarly decreases cyclin transcripts, identifying β-catenin as an Nr5a2 cofactor in this process.\",\n      \"method\": \"Conditional knockout (Nr5a2-Amhr2-Cre), BrdU incorporation, PCNA immunostaining, FACS, microarray, ML180 pharmacological inhibition, β-catenin inhibitor treatment\",\n      \"journal\": \"Journal of the Endocrine Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with pharmacological corroboration and mechanistic pathway analysis\",\n      \"pmids\": [\"29379893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LRH-1 (NR5A2) directly binds to LRH-1 binding sites in the FASLG (CD95L/FasL) promoter and drives FASLG promoter activity in T cells; mutation of LRH-1 binding sites reduces FASLG promoter activity; pharmacological inhibition of LRH-1 decreases activation-induced FasL expression and FasL-mediated T cell apoptosis and cytotoxicity.\",\n      \"method\": \"Chromatin immunoprecipitation, promoter reporter assays with binding site mutagenesis, pharmacological inhibition, T cell functional assays, mouse hepatitis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP plus mutagenesis plus in vivo pharmacological model, multiple orthogonal methods\",\n      \"pmids\": [\"28406481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NR5A2 undergoes transcriptional relocation in Nr5a2+/- pancreatic tissue from differentiation-specific to inflammatory gene promoters; this promotes AP-1-dependent inflammatory gene transcription; pancreatic deletion of Jun rescues the pre-inflammatory phenotype and NR5A2 binding to inflammatory gene promoters; NR5A2 thus links differentiation and inflammatory programs.\",\n      \"method\": \"Global transcriptomic analysis, ChIP in pancreatic tissue, conditional Jun knockout rescue, NR5A2 ChIP-seq\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq with genetic rescue (Jun KO) and transcriptomics, multiple orthogonal approaches\",\n      \"pmids\": [\"29443959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LRH-1/NR5A2 is required for T cell maturation and function: T cell-specific deletion causes drastic loss of mature peripheral T cells, strongly reduced activation-induced proliferation in vitro and in vivo, and failure to control viral infections by CD8+ T cells; LRH-1 is induced in T lymphocytes upon stimulation.\",\n      \"method\": \"T cell-specific LRH-1 conditional knockout mice, T cell proliferation assays, antigen immunization, viral infection challenge\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with multiple in vitro and in vivo functional readouts\",\n      \"pmids\": [\"31328159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NR5A2 synergizes with coactivator NCOA3 to upregulate NRF2 expression, thereby preventing BET inhibitor (BETi)-induced ferroptosis in breast cancer cells; inhibition of NR5A2 or NCOA3 enhances BETi anti-cancer effects in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown, overexpression, small molecule inhibitors, Western blot, in vivo xenograft model\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — functional assays in multiple systems but interaction between NR5A2 and NCOA3 not biochemically reconstituted in abstract\",\n      \"pmids\": [\"32536370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRH-1/NR5A2 inhibition reduces LPS-induced pro-inflammatory cytokine production in macrophages by downregulating LRH-1 targets glucokinase and glutaminase-2, thereby impairing mitochondrial ATP production and LPS-induced macrophage activation; in vivo LRH-1 inhibition reduces TNF production and liver damage in macrophage-dependent hepatitis.\",\n      \"method\": \"LRH-1 pharmacological inhibition, siRNA knockdown, metabolic assays (mitochondrial ATP), cytokine measurement, mouse hepatitis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic loss-of-function with mechanistic metabolic readout, single lab\",\n      \"pmids\": [\"32111818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nr5a2 depletion from granulosa cells of primordial follicles impairs activation of primordial follicles into the growing pool: cKO ovaries have more primordial and fewer primary follicles; Nr5a2 loss induces changes in quiescence markers, follicle activation inhibitors, and regulators of migration/EMT.\",\n      \"method\": \"Conditional knockout from primordial follicles, follicle enumeration, in vitro culture, RNA sequencing\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with transcriptomic analysis, single lab\",\n      \"pmids\": [\"33441767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The combined activity of Esrrb and Nr5a2 is essential for naïve mouse ESC self-renewal: double depletion causes pluripotency network collapse and differentiation; Esrrb and Nr5a2 co-occupy a large common set of regulatory elements and control binding of Oct4, Sox2, and Nanog to DNA.\",\n      \"method\": \"Conditional double knockout in ESCs, ChIP-seq, transcriptome analysis\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide ChIP-seq showing mechanistic control of pluripotency factor binding\",\n      \"pmids\": [\"34397088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NR5A2/LRH-1 regulates the PTGS2-PGE2-PTGER1 pathway in pancreatic islets: LRH-1 ablation in beta cells blocks beta cell proliferation and abolishes agonist (BL001) anti-diabetic action; LRH-1 activation induces PTGS2/COX2 expression, increasing PGE2 levels; PGE2 acts via PTGER1 receptor to confer islet survival against cytokine-induced apoptosis.\",\n      \"method\": \"Beta cell-specific conditional knockout, agonist (BL001) treatment, PTGS2 inhibition, PTGER1 antagonist, cytochrome c release, PARP cleavage assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO combined with pharmacological dissection defining a multi-step signaling pathway\",\n      \"pmids\": [\"35602948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nr5a2 is an essential pioneer factor for zygotic genome activation (ZGA) in mouse two-cell embryos: Nr5a2 is required for progression beyond the two-cell stage; it binds its motif within SINE B1/Alu retrotransposable elements in cis-regulatory regions of ZGA genes; NR5A2 promotes chromatin accessibility during ZGA and binds nucleosomal DNA in vitro; chemical inhibition indicates 72% of ZGA genes are regulated by Nr5a2.\",\n      \"method\": \"De novo motif search, Nr5a2 knockout in mouse embryos, ATAC-seq (chromatin accessibility), ChIP/CUT&RUN in embryos, in vitro nucleosome binding assays, chemical inhibition\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic KO plus in vitro nucleosome binding plus genome-wide chromatin accessibility, multiple orthogonal methods\",\n      \"pmids\": [\"36423263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR5A2 connects ZGA to the first lineage segregation: Nr5a2 knockdown/knockout causes arrest at morula stage with impaired 4-8C gene activation; NR5A2 binds cis-regulatory elements enriched for B1 elements in both 2C and 8C embryos; NR5A2 is not required for global opening of 2C binding sites but is essential for opening 8C-specific sites; NR5A2 directly regulates key pluripotency genes (Nanog, Pou5f1/Oct4), primitive endoderm genes (Gata6), and trophectoderm genes (Tead4, Gata3) at the 8C stage.\",\n      \"method\": \"Nr5a2 knockdown and knockout in mouse embryos, genome-wide ChIP/CUT&RUN, ATAC-seq, transcriptome analysis\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with genome-wide chromatin binding and accessibility analysis in embryos\",\n      \"pmids\": [\"37935903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of human NR5A2 bound to a nucleosome reveals the conserved CTE (carboxy-terminal extension) loop of the NR5A2 DNA-binding domain competes with a DNA minor groove anchor of the nucleosome, releasing entry-exit site DNA; mutational analysis showed NR5A2 D159 of the CTE is dispensable for free DNA binding but required for stable nucleosome association and persistent DNA unwrapping, establishing the mechanism of NR5A2 pioneer activity.\",\n      \"method\": \"Cryo-electron microscopy of NR5A2-nucleosome complex, site-directed mutagenesis (D159), nucleosome binding assays, DNA unwrapping assays\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with mutagenesis and functional binding assays defining pioneer mechanism\",\n      \"pmids\": [\"38409506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NR5A2 acts as a bipotency activator in totipotent (2-8 cell) mouse embryos: NR5A2 binds and activates both early ICM and trophectoderm lineage genes at the 8-cell stage; upon trophoblast commitment, NR5A2 transitions from ICM to TE gene regulation; NR5A2 binding at 8C-specific sites controls key pluripotency and TE regulatory genes.\",\n      \"method\": \"Conditional Tfap2c and Nr5a2 depletion in mouse embryos, ChIP-seq in embryos at multiple developmental stages, transcriptomic analysis\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq across developmental stages with genetic loss-of-function in embryos\",\n      \"pmids\": [\"38243114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nr5a2-/- mouse embryos arrest at early morula stage (not two-cell stage): Nr5a2 plays a minor role in ZGA but is a master regulator at the 8-cell stage controlling expression of lineage-specifying transcription factors and genes involved in mitosis, telomere maintenance, and DNA repair; Nr5a2-deficient embryos show frequent mitotic failure and chromosome segregation defects.\",\n      \"method\": \"Nr5a2 conditional and constitutive knockout mouse models, single-embryo transcriptomics, immunofluorescence for mitotic markers\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models resolving prior conflicting data, with transcriptomic and cytological phenotype analysis\",\n      \"pmids\": [\"39361745\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NR5A2 (LRH-1/FTZ-F1 family) is a monomeric orphan nuclear receptor whose CTE/Ftz-F1 box domain mediates both sequence-specific DNA binding and pioneer activity via nucleosome minor groove anchor competition; it acts as a master transcriptional regulator at distinct developmental stages—including zygotic genome activation, first lineage segregation, pancreatic organogenesis, and ovarian folliculogenesis—where it directly controls gene programs for pluripotency (activating Nanog, Oct4), steroidogenesis (Cyp11a1, Star, Scarb1), acinar differentiation (Ptf1a, Rbpjl), and inflammation resolution (PTGS2-PGE2-PTGER1 axis), while its transcriptional activity is modulated by LXXLL-motif cofactors (e.g., Ftz, Prox1), coactivators (NCOA3, p160/SRC), post-translational SUMOylation, phospholipid ligands (PIP3), and antagonism by inflammatory transcription factors (c-Jun, NF-κB).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NR5A2 (LRH-1; FTZ-F1 family) is a monomeric orphan nuclear receptor that functions as a sequence-specific, pioneer transcription factor governing developmental gene programs from the earliest embryo through organogenesis [#43, #45, #29]. Its DNA-binding region combines a zinc finger with a conserved C-terminal FTZ-F1/CTE box that confers monomeric recognition of the extended PyCAAGG-type motif and binds DNA without an obligate ligand [#1, #5, #4]. Structural work established that the FTZ-F1 box folds into a helix packing against the DBD to enable long-range communication with the ligand-binding domain and full transcriptional and coactivator output [#17], while cryo-EM of an NR5A2-nucleosome complex showed the CTE loop competes with the nucleosomal DNA minor-groove anchor to release entry-exit DNA, defining the structural basis of NR5A2 pioneer activity [#45]. In the early embryo NR5A2 binds its motif within SINE B1/Alu elements at cis-regulatory regions, opens chromatin, and acts as a master regulator of zygotic genome activation and the first lineage segregation, directly controlling pluripotency genes (Nanog, Pou5f1/Oct4) and lineage factors (Gata6, Tead4, Gata3), with loss causing morula-stage arrest, mitotic failure, and segregation defects [#43, #44, #47, #46]; consistent with this it can replace Oct4 in somatic reprogramming and, with Esrrb, sustains naive ESC self-renewal by controlling Oct4/Sox2/Nanog binding [#21, #41]. In organogenesis NR5A2 drives pancreatic progenitor expansion and acinar differentiation through mutually reinforcing regulation with PTF1A and a network including MYC, GATA4, FOXA2, RBPJL and MIST1, and its loss destabilizes the acinar state and accelerates Kras-driven metaplasia and inflammation [#29, #24, #36]. In the ovary NR5A2 controls steroidogenesis and luteal progesterone synthesis via cholesterol-transport genes (Scarb1, Ldlr, Star) and granulosa cell proliferation [#28, #20, #34]. NR5A2 transcriptional output is modulated by LXXLL/homeodomain cofactors (Ftz, Prox1), p160/SRC and NCOA3 coactivators, SUMOylation, and phospholipid (PIP3) binding within its LBD, and is antagonized by the inflammatory transcription factors c-Jun/AP-1 and NF-\\u03baB [#14, #16, #18, #21, #31, #30, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Defined how the receptor achieves sequence-specific DNA recognition, establishing that an FTZ-F1 family receptor reads its element as a monomer using a dedicated basic box plus zinc finger.\",\n      \"evidence\": \"Gel mobility shift competition with mutant peptides for Drosophila FTZ-F1\",\n      \"pmids\": [\"1448096\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address mammalian ortholog function in vivo\", \"No structural model of the FTZ-F1 box\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Extended the family to mammals and showed the vertebrate receptor binds its element as a monomer without an obligate ligand and activates target promoters, with a C-terminal truncation acting dominant-negative.\",\n      \"evidence\": \"cDNA cloning, Kd measurement, and reporter assays with truncation mutants for rat FTF\",\n      \"pmids\": [\"8668203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ligand undefined\", \"Physiological target genes beyond AFP not yet mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the human gene (NR5A2/hB1F) as an FTZ-F1-family orphan receptor with defined DNA binding, transactivation, chromosomal locus, and splice isoforms.\",\n      \"evidence\": \"Yeast one-hybrid, binding and transactivation reporter assays, RT-PCR, FISH\",\n      \"pmids\": [\"9786908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous human target genes not yet defined\", \"No in vivo function established\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Resolved the cofactor logic of the receptor, showing homeodomain partners engage both the DBD and the AF-2 surface via LXXLL-like motifs, and that mammalian SF-1 can substitute functionally in flies.\",\n      \"evidence\": \"In vitro pulldowns, domain mapping, and in vivo genetic rescue in Drosophila\",\n      \"pmids\": [\"11520662\", \"11592991\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify vertebrate equivalents of these cofactors at the time\", \"Structural basis of AF-2 docking not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided the structural basis for DBD-LBD functional communication, showing the FTZ-F1 box helix is required for transcriptional activity and coactivator enhancement even though it does not contact DNA.\",\n      \"evidence\": \"X-ray crystallography of the human LRH-1 DBD-DNA complex with mutagenesis and reporter/coactivator assays\",\n      \"pmids\": [\"16289203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address nucleosomal DNA engagement\", \"Mechanism of long-range communication not fully defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the in vivo requirement for NR5A2 in mammalian development, showing it acts in extraembryonic tissues for epiblast gastrulation.\",\n      \"evidence\": \"Knockout mice with tetraploid complementation and marker analysis\",\n      \"pmids\": [\"17075876\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve preimplantation roles\", \"Direct target genes at gastrulation not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked NR5A2 dosage causally to luteal steroidogenesis, showing reduced progesterone underlies the fertility defect and is rescued by progesterone supplementation.\",\n      \"evidence\": \"Nr5a2 heterozygous mice with hormone measurement and pharmacological rescue\",\n      \"pmids\": [\"17409375\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct steroidogenic target genes not yet identified\", \"Cell-autonomous requirement not separated from systemic effects\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected NR5A2 to the pluripotency network, showing it can replace Oct4 in reprogramming, shares targets with Sox2/Klf4, activates Nanog, and is negatively regulated by SUMOylation.\",\n      \"evidence\": \"Reprogramming assays, sumoylation-site mutagenesis, and genome-wide ChIP-chip in mouse cells\",\n      \"pmids\": [\"20096661\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish requirement in normal embryo pluripotency at this stage\", \"SUMO-target sites mapped only functionally\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined NR5A2 as a guardian of pancreatic acinar identity whose loss promotes metaplasia, inflammation, and Kras-driven neoplasia, linking it to NF-\\u03baB/STAT3 signaling.\",\n      \"evidence\": \"Conditional and heterozygous knockout mice with pancreatitis and Kras models, pathway analysis (two concurrent studies)\",\n      \"pmids\": [\"23645620\", \"23598351\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct target genes mediating acinar maintenance not yet mapped\", \"Mechanism connecting NR5A2 loss to NF-\\u03baB/STAT3 hyperactivation unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established NR5A2 as a direct controller of pancreatic organogenesis through a mutually reinforcing regulatory network with PTF1A and other lineage factors.\",\n      \"evidence\": \"Conditional inactivation with genome-wide ChIP and co-binding analysis at shared regulatory regions\",\n      \"pmids\": [\"25063451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve pioneer versus settler binding mode in this context\", \"Hierarchy of NR5A2 versus PTF1A initiation not fully ordered\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined direct ovarian steroidogenic and ovulatory targets, linking NR5A2 to Pgr and cholesterol-transport genes (Scarb1, Ldlr, Star) required for progesterone synthesis and ovulation.\",\n      \"evidence\": \"Granulosa-specific conditional knockout with hormone and gene expression analysis\",\n      \"pmids\": [\"24552399\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect regulation of Pgr not fully separated\", \"Cofactor dependence in granulosa cells not addressed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed inflammatory signaling antagonizes NR5A2 directly, with c-Jun and NF-\\u03baB physically interacting with NR5A2 to repress its steroidogenic target Cyp11a1.\",\n      \"evidence\": \"Reporter assays, protein interaction, dominant-negative experiments, and a mouse colitis model\",\n      \"pmids\": [\"24570488\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NR5A2 repression by c-Jun/NF-\\u03baB unknown\", \"Generality across NR5A2 target loci not established\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a phospholipid ligand mode, showing PIP3 binds the NR5A2 LBD with its tails buried and head group surface-exposed, stabilizing the domain.\",\n      \"evidence\": \"X-ray crystallography of the LBD-PIP3 complex with affinity and thermal stability measurement\",\n      \"pmids\": [\"26416531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of PIP3 occupancy in vivo not demonstrated\", \"Effect on coactivator recruitment not directly tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened the developmental remit of NR5A2 to neural stem cell fate, where it directs neurogenesis over astrogliogenesis through Ink4/Arf, Prox1, Notch1 and JAK/STAT.\",\n      \"evidence\": \"Gain- and loss-of-function in primary NSCs and mouse embryos with target/pathway analysis\",\n      \"pmids\": [\"27447294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect regulation of listed targets not fully separated\", \"Upstream control of NR5A2 in neural lineages partly inferred\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended NR5A2 function to immune regulation, showing it directly drives FASLG transcription to control T cell apoptosis and cytotoxicity.\",\n      \"evidence\": \"ChIP, promoter mutagenesis, pharmacological inhibition, and a mouse hepatitis model\",\n      \"pmids\": [\"28406481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactor requirements at FASLG not defined\", \"Endogenous ligand controlling this activity unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a regulatory switch in which reduced NR5A2 relocates from differentiation to inflammatory gene promoters in an AP-1-dependent manner, mechanistically uniting differentiation and inflammation control.\",\n      \"evidence\": \"Transcriptomics, NR5A2 ChIP-seq, and conditional Jun knockout rescue in pancreas\",\n      \"pmids\": [\"29443959\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for promoter relocation unresolved\", \"Whether relocation reflects altered cofactor availability not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a cell-intrinsic requirement for NR5A2 in T cell maturation, proliferation, and antiviral CD8+ responses.\",\n      \"evidence\": \"T cell-specific conditional knockout with proliferation, immunization, and viral challenge assays\",\n      \"pmids\": [\"31328159\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets in T cells not mapped here\", \"Relationship to FASLG regulation not integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined a multi-step islet survival pathway, showing NR5A2 induces PTGS2/COX2 to raise PGE2 acting through PTGER1 to protect beta cells and drive proliferation.\",\n      \"evidence\": \"Beta cell-specific knockout with agonist treatment and pharmacological dissection of PTGS2/PTGER1\",\n      \"pmids\": [\"35602948\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NR5A2 occupancy at Ptgs2 not shown\", \"Translation of agonist effects to human islets not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified NR5A2 as an essential pioneer factor for zygotic genome activation, binding its motif in SINE B1/Alu elements to open chromatin and bind nucleosomal DNA.\",\n      \"evidence\": \"Embryo knockout, ATAC-seq, ChIP/CUT&RUN, in vitro nucleosome binding, and chemical inhibition\",\n      \"pmids\": [\"36423263\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact arrest stage and extent of ZGA dependence later contested\", \"Structural basis of nucleosome engagement not yet defined here\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconciled embryonic phenotypes and clarified NR5A2 as primarily an 8-cell/morula-stage master regulator of lineage factors, mitosis, telomere maintenance and DNA repair, with loss causing chromosome segregation defects.\",\n      \"evidence\": \"Multiple knockout models with single-embryo transcriptomics and mitotic immunofluorescence, plus ChIP-seq across stages defining bipotency activation of ICM and TE genes\",\n      \"pmids\": [\"39361745\", \"37935903\", \"38243114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking NR5A2 to mitotic/DNA-repair gene control unresolved\", \"How NR5A2 transitions from ICM to TE regulation not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the structural mechanism of NR5A2 pioneer activity, showing the CTE loop competes with a nucleosomal minor-groove DNA anchor to release entry-exit DNA, with D159 required for stable nucleosome engagement.\",\n      \"evidence\": \"Cryo-EM of the NR5A2-nucleosome complex with D159 mutagenesis and DNA unwrapping assays\",\n      \"pmids\": [\"38409506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define how cofactors stabilize the unwrapped state in cells\", \"Sequence determinants of nucleosomal site selection not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous physiological ligand that tunes NR5A2 activity across these contexts, and how a single pioneer receptor is directed to context-specific gene programs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No defined endogenous ligand beyond in vitro PIP3 binding\", \"Determinants of context-specific target selection unknown\", \"Mechanism coupling chromatin opening to downstream coactivator recruitment in vivo not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 4, 5, 17, 43, 45]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 11, 29, 36, 43]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [31]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [45]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [17, 43, 36]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [45, 43]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 29, 36, 43]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [43, 44, 45]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [29, 33, 32, 47]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [28, 39]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [35, 37, 30]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTF1A\", \"ESRRB\", \"NCOA3\", \"JUN\", \"PROX1\", \"HNF1\", \"FTZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}