{"gene":"SF1","run_date":"2026-06-10T07:46:31","timeline":{"discoveries":[{"year":1996,"finding":"Mammalian splicing factor SF1 (ZFM1/ZNF162) consists of a single ~75 kDa polypeptide encoded by alternatively spliced mRNAs. It contains a KH domain and zinc knuckle required for RNA binding and binds directly to RNA with preference for G- and U-rich sequences. Multiple SF1 isoforms expressed via baculovirus showed comparable activities in pre-splicing complex assembly.","method":"cDNA isolation, baculovirus expression, RNA binding assays, in vitro splicing complex assembly","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical assays (RNA binding, complex assembly), multiple isoforms tested, replicated across constructs in one rigorous study","pmids":["8752089"],"is_preprint":false},{"year":1991,"finding":"SF1 (splicing factor 1) is an essential protein factor required for the formation of the pre-splicing complex (early ATP-dependent spliceosomal complex), functioning together with SF3 and U2AF, and is essential for production of spliced RNA.","method":"Chromatographic fractionation of HeLa nuclear extracts, in vitro splicing assays, pre-splicing complex assembly","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with fractionated components; requirement established by depletion and complementation","pmids":["1827409"],"is_preprint":false},{"year":1998,"finding":"Mammalian SF1 (mBBP/SF1) binds specifically to the branchpoint sequence and interacts with U2AF65, which binds the adjacent polypyrimidine tract. This protein-protein interaction promotes cooperative binding to a branchpoint sequence-polypyrimidine tract RNA, contributing to initial branchpoint sequence recognition. The third RBD (degenerate RRM) of U2AF65 is essential for the SF1 interaction.","method":"RNA binding assays, protein-protein interaction assays, cooperative binding experiments, domain mapping","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical reconstitution of cooperative RNA binding, domain-mapping of the interaction, multiple orthogonal assays","pmids":["9512519"],"is_preprint":false},{"year":1998,"finding":"The KH domain of human SF1 is the major determinant for RNA binding and is essential for spliceosome assembly. The region N-terminal to the KH domain mediates the interaction with U2AF65. Yeast SF1 similarly interacts with Mud2p (the yeast U2AF65 homologue) via its conserved C-terminal degenerate RRM. The KH domain function is conserved between human and yeast SF1.","method":"Domain deletion analysis, chimeric construct analysis, yeast two-hybrid, in vitro spliceosome assembly","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple domain-mapping experiments and chimeric constructs in both human and yeast systems, in vitro assembly assays","pmids":["9582097"],"is_preprint":false},{"year":1999,"finding":"SF1 (splicing factor 1) is phosphorylated by cGMP-dependent protein kinase I (PKG-I) at Ser20. This phosphorylation inhibits the SF1-U2AF65 interaction and blocks pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating Ser20 is essential for binding. Phosphorylation of SF1 on Ser20 occurs in cultured neuronal cells and is increased by cGMP analogue treatment.","method":"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, pre-spliceosome assembly assay, cell-based phosphorylation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay with mutagenesis, functional spliceosome assembly readout, and cell-based validation; multiple orthogonal methods","pmids":["10449420"],"is_preprint":false},{"year":1998,"finding":"ZFM1 (identical to splicing factor SF1) functions as a transcriptional repressor. Its N-terminal 137 amino acids contain a repression domain. ZFM1 interacts with the transcription activation domain of SSAP (a sea urchin transcription factor) and represses Gal4-GQC-mediated transcription; only activated, not basal, transcription is affected.","method":"Yeast two-hybrid, functional transcription repression assays in mammalian cells, Gal4 fusion assays, domain mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional reporter assays in mammalian cells; single lab but multiple assays","pmids":["9506990"],"is_preprint":false},{"year":1998,"finding":"ZFM1/SF1 interacts with the EWS transcriptional activation domain (NTD) via a 37 amino acid region. Overexpression of ZFM1 in HepG2 cells represses EWS-NTD-driven transcription. ZFM1 also interacts with TLS and hTAFII68, proteins homologous to EWS. This suggests ZFM1 negatively modulates transcription coordinated by EWS/TLS/TAF cofactors.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, reporter gene assays in HepG2 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — GST pull-down plus yeast two-hybrid plus functional repression assay; single lab, multiple orthogonal methods","pmids":["9660765"],"is_preprint":false},{"year":2001,"finding":"The transcription elongation factor CA150 directly binds to SF1 through its WW1 and WW2 domains interacting with a novel proline-rich motif in the C-terminal half of SF1. This interaction is required for efficient CA150-mediated repression of transcription elongation. CA150 also binds to the phosphorylated CTD of RNAPII via its FF repeats, suggesting SF1 targets the nascent transcript to recruit CA150.","method":"Protein-protein interaction mapping, co-immunoprecipitation, transcription repression reporter assays, domain deletion analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding mapped by domain analysis plus functional repression assays; single lab, multiple methods","pmids":["11604498"],"is_preprint":false},{"year":2006,"finding":"SF1 is highly phosphorylated in mammalian cells on two serines within an SPSP motif (at the junction between its U2AF65 and RNA binding domains) by the kinase KIS. KIS interacts with SF1 via its UHM domain, which is required for efficient SPSP phosphorylation. SPSP phosphorylation by KIS increases SF1 binding to U2AF65 and enhances formation of the ternary SF1-U2AF65-RNA complex.","method":"Mass spectrometry phosphorylation mapping, in vitro kinase assay, protein-protein interaction assays, domain mutagenesis, ternary complex formation assay","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay with defined substrate site, domain mapping, functional ternary complex assay; multiple orthogonal methods in one study","pmids":["16420481"],"is_preprint":false},{"year":2015,"finding":"SF1 interacts with SURP domain-containing U2 snRNP proteins (SAP49/SF3b4 and SF3b1-related factors) via a short evolutionarily conserved region. Co-immunoprecipitation from HeLa extracts found nearly all U2 snRNP proteins associated with SF1. Depletion of SF1 reduced A complex (spliceosome) formation, rescued by recombinant SF1 containing the SURP-interaction domain but only partially by SF1 lacking this domain. This shows SF1 can recruit U2 snRNP to the spliceosome during E complex formation.","method":"Co-immunoprecipitation from HeLa extracts, yeast two-hybrid, SF1 depletion and complementation, spliceosomal complex assembly assay","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — functional depletion/rescue assays combined with reciprocal co-IP and yeast two-hybrid; multiple orthogonal methods in one study","pmids":["26420826"],"is_preprint":false},{"year":2015,"finding":"PRPF40B directly interacts with SF1 and associates with U2AF65. PRPF40B colocalizes with SF1 and U2AF65 in nuclear speckles. PRPF40B modulates alternative splice site selection and depletion of PRPF40B increases Fas/CD95 receptor levels and cell apoptosis.","method":"Co-immunoprecipitation, yeast two-hybrid, colocalization by immunofluorescence, alternative splicing reporter assays, siRNA knockdown","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction established by co-IP and yeast two-hybrid; functional consequences via splicing reporter and knockdown; single lab","pmids":["25605964"],"is_preprint":false},{"year":1999,"finding":"Drosophila SF1 (DmSF1) and C. elegans SF1 (CeSF1) contain N-terminal RS domains enriched in Ser, Arg, Lys, and Asp residues, unlike their yeast and mammalian counterparts. DmSF1 lacking its N-terminus is functional in prespliceosome formation in a HeLa splicing system, showing the KH domain function is conserved. CeSF1 is essential for viability (injection of dsRNA causes embryonic lethality in C. elegans), establishing SF1 as essential for metazoan development.","method":"cDNA isolation, RNAi (C. elegans), in vitro splicing reconstitution in HeLa extracts, protein interaction assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — genetic loss-of-function (lethality) in C. elegans combined with in vitro functional reconstitution; two orthogonal approaches","pmids":["10606272"],"is_preprint":false},{"year":2014,"finding":"SF1 and the RNA-binding protein Celf3 co-localize in novel nuclear bodies (CS bodies) in neuroblastoma Neuro2A cells. The lncRNA Gomafu binds both SF1 and Celf3 but forms distinct nuclear bodies separate from CS bodies, suggesting Gomafu indirectly modulates SF1 function by sequestering it into separate compartments.","method":"Cross-link RNA precipitation, knockdown, immunofluorescence colocalization, nuclear body imaging","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct RNA-protein binding confirmed by CLIP; colocalization by imaging; functional consequence inferred; single lab","pmids":["25145264"],"is_preprint":false},{"year":2001,"finding":"Down-regulation of ZFM1/SF1 (splicing factor 1) by IL-1β and TNF-α in vascular smooth muscle cells promotes cell proliferation and expression of pro-inflammatory gene products (MCP-1, VCAM-1). Antisense oligonucleotide suppression of ZFM1 protein mimics cytokine-stimulated SMC proliferation. In an atherosclerosis mouse model, ZFM1 abundance was decreased in proliferating arterial SMC.","method":"Suppression subtractive hybridization, antisense oligonucleotides, cell proliferation assay, in vivo atherosclerosis model, Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antisense knockdown with defined proliferation phenotype, corroborated by in vivo model; single lab, multiple methods","pmids":["11748220"],"is_preprint":false},{"year":2007,"finding":"SF1 (splicing factor 1) was identified as a novel component of the β-catenin/TCF-4 transcriptional complex. Overexpression of SF1 inhibited the transcriptional activity of this complex and markedly suppressed β-catenin-evoked colony formation in HEK293 cells. Homozygous SF1 knockout mice die before E8.5; heterozygous Sf1+/- mice are viable but more susceptible to azoxymethane-induced colon tumorigenesis.","method":"Co-immunoprecipitation (complex identification), reporter assay, colony formation assay, gene trap knockout mice, carcinogen-induced tumor model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex membership established by co-IP; functional consequence in vitro (reporter + colony assay) and in vivo (knockout + carcinogen model); single lab","pmids":["17900258"],"is_preprint":false},{"year":2008,"finding":"SUMO modification of SF-1 (NR5A1) at Lys119 (adjacent to the DNA-binding domain) results in a marked and selective loss of DNA binding to noncanonical SF-1 target genes (e.g. inhibin-α). DNA binding and sumoylation of Lys119 are mutually exclusive. Sumoylation at Lys194 (adjacent to the LBD) modestly reduces Ser203 phosphorylation but does not greatly impair coregulator recruitment or conformation. The K119R mutant is selectively recruited to SUMO-sensitive sites in the endogenous inhibin-α promoter, leading to increased transcription.","method":"In vitro sumoylation, site-directed mutagenesis (K119R, K194R), NMR structural analysis of sumoylated LBD, chromatin immunoprecipitation, transcriptional reporter assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro sumoylation combined with structural (NMR), ChIP, and functional reporter assays; multiple orthogonal methods in one study","pmids":["18838537"],"is_preprint":false},{"year":2017,"finding":"SF1 SUMOylation increases binding of DAX1 to SF1 (without directly influencing SF1 DNA binding), thereby enhancing transcriptional repression of the fetal adrenal enhancer (FAdE). SUMOylation-deficient SF1 mice and Dax1 knockout mice both show delayed regression of the postnatal fetal adrenal cortex (X-zone) and prolonged FAdE expression, defining a cooperative repressor function.","method":"SUMOylation-deficient knock-in mice, Dax1 knockout mice, reporter mouse (FAdE-lacZ), in vitro protein-protein interaction assays","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic models (two independent mouse lines) with defined phenotype, supported by in vitro interaction data; two labs' approaches converge","pmids":["28893949"],"is_preprint":false},{"year":2018,"finding":"Tat-SF1 contains a U2AF homology motif (UHM) protein-protein interaction module (determined by 1.1 Å crystal structure). Tat-SF1 preferentially and directly binds the SF3b1 subunit of the U2 snRNP via a canonical UHM-ULM interface (Tat-SF1 binding pocket for SF3b1 Trp338). SF3b1 regulates Tat-SF1 protein levels, and these two factors influence expression of overlapping transcripts.","method":"Crystal structure (1.1 Å, 1.9 Å, 2.1 Å resolution), co-immunoprecipitation, binding affinity measurements, siRNA knockdown, transcriptomics","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures of the complex with mutagenic validation of the interface; orthogonal functional assays; rigorous study","pmids":["30567737"],"is_preprint":false},{"year":1999,"finding":"Ptx1 interacts directly with SF-1 (NR5A1/steroidogenic factor 1) through its C-terminus binding the N-terminal half of SF-1. This interaction requires SF-1 DNA binding and results in transcriptional enhancement equivalent to a constitutively active SF-1 mutant, mimicking the effect of a putative SF-1 ligand. This synergism is observed on the LH-beta and MIS promoters.","method":"GST pull-down, co-immunoprecipitation, transcriptional reporter assays, constitutively active SF-1 mutant comparison, domain mapping","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct physical interaction established by GST pulldown plus functional transcription assays; single lab, two orthogonal methods","pmids":["10369682"],"is_preprint":false},{"year":1999,"finding":"Egr-1 interacts directly with both Ptx1 and SF-1, and these interactions enhance Ptx1- and SF-1-induced LHβ transcription. GnRH stimulates Egr-1 (but not Ptx1 or SF-1) expression via the PKC pathway, establishing Egr-1 as a transcriptional mediator of GnRH signaling that converges on SF-1 activity.","method":"GST pull-down (direct interaction), co-transfection reporter assays, PKC activation studies, GnRH stimulation experiments","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction by GST pulldown combined with functional reporter assays and GnRH stimulation; single lab","pmids":["10082522"],"is_preprint":false},{"year":2000,"finding":"PNRC (proline-rich nuclear receptor coregulatory protein) interacts directly with SF1 (steroidogenic factor 1) in a ligand-independent manner via a 23-amino acid C-terminal sequence containing an SH3-binding motif (SDPPSPSP), with the two conserved prolines required for interaction. PNRC functions as a coactivator to enhance SF1-mediated transcriptional activation. Direct contact between PNRC and SF1 was confirmed by GST pull-down.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transcriptional reporter assays, domain mutagenesis","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction confirmed by GST pulldown; functional activation assays; domain mutants; single lab","pmids":["10894149"],"is_preprint":false},{"year":2002,"finding":"WT1 (specifically the -KTS isoform) directly binds to and transactivates the Sf1 promoter, establishing WT1 as a direct upstream activator of SF1 expression. LHX9 also functions as a direct activator of the Sf1 gene. Genetic experiments placed Wt1 and Lhx9 upstream of Sf1 in the gonadal development pathway.","method":"Biochemical binding assays, transcriptional reporter assays, genetic epistasis (gonad-specific knockout models), promoter analysis","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding and transactivation combined with genetic epistasis; two independent upstream regulators identified; replicated approaches","pmids":["12130543"],"is_preprint":false},{"year":2014,"finding":"FOXL2 transcriptionally represses Sf1 expression by directly binding a conserved FOXL2 binding site in the Sf1 proximal promoter and antagonizing WT1-KTS-mediated activation. Mutation of the FOXL2 binding site abolishes repression in reporter assays. In Foxl2-null mice, Sf1 expression is increased ~2-fold in XX fetal gonads.","method":"Quantitative RT-PCR, reporter assays, in vitro ChIP, site-directed mutagenesis, Foxl2-null mouse model","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, mutant reporter assay, and in vivo mouse model; single lab, multiple methods","pmids":["24451388"],"is_preprint":false},{"year":2016,"finding":"WT1 represses Sf1 expression by directly binding to the Sf1 promoter region. When WT1 binding sites are mutated, the repressive function is abolished. Loss of Wt1 before sex determination causes upregulation of Sf1, leading to differentiation of somatic cells into steroidogenic cells instead of supporting (Sertoli/granulosa) cells.","method":"Conditional Wt1 knockout mice (temporal deletion), promoter binding assay, site-directed mutagenesis of WT1 binding sites, histological and gene expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct promoter binding with mutagenesis confirmation, combined with in vivo conditional knockout with clear cell lineage phenotype; multiple orthogonal methods","pmids":["27888191"],"is_preprint":false},{"year":2008,"finding":"SRY binds to multiple elements within a Sox9 gonad-specific enhancer (Tesco) together with SF1 (NR5A1). SF1 and SRY cooperatively upregulate Sox9 expression; SOX9 subsequently also binds the same enhancer along with SF1 to maintain its own expression after SRY expression ceases (feedforward loop). Mutation and sex-reversal studies confirmed that cooperative SF1/SRY binding to the enhancer is required for male sex determination.","method":"ChIP, enhancer mutation studies, co-transfection reporter assays, sex-reversal genetic experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP binding data, functional enhancer mutations, and in vivo sex-reversal genetic validation; multiple orthogonal methods; high-impact study","pmids":["18454134"],"is_preprint":false},{"year":2011,"finding":"Ectopic activation of Wnt/β-catenin signaling in male gonads reduces SF1 binding to the Tesco (Sox9 testis) enhancer without altering SF1 mRNA or protein levels, abolishing Sox9 expression. SF1 binding to the Cyp11a1 promoter (a Leydig cell target) was not affected. This demonstrates that Wnt/β-catenin signaling selectively prevents SF1 from accessing specific enhancers.","method":"ChIP for SF1 at Tesco enhancer and Cyp11a1 promoter, Wnt/β-catenin pathway activation/inhibition, embryonic gonad culture, gene expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating selective loss of SF1 binding at specific loci; supported by gene expression data; single lab","pmids":["22128028"],"is_preprint":false},{"year":2012,"finding":"Excess DAX1 antagonizes SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of the Sox9 testis enhancer (Tesco) by reducing SF1 binding to Tesco. This provides the molecular mechanism for dosage-sensitive sex reversal: increased DAX1 impairs SF1-mediated Sox9 activation.","method":"Reporter assays in cultured cells, ChIP for SF1 at Tesco, transgenic mice overexpressing Dax1, genetic epistasis with Sox9 heterozygotes","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP showing reduced SF1 binding, reporter assays with dose-response, and in vivo transgenic validation; single lab","pmids":["22294746"],"is_preprint":false},{"year":2009,"finding":"GPR30/GPER activation (by tamoxifen analogue STX) increases cellular pools of phosphatidylinositol (3,4,5) triphosphate via PI3K signaling, which activates SF-1 (NR5A1) transcription, promotes endometrial cell proliferation, and induces the SF-1 target gene aromatase. This establishes a GPR30→PI3K→SF-1 signaling axis.","method":"PI3K/MAPK pathway activation assays, SF-1 transcription reporter assays, cell proliferation assays, siRNA for GPR30, PI3P measurement","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological activation with GPR30-specific compound, siRNA knockdown validation, functional proliferation assay; single lab","pmids":["19549922"],"is_preprint":false},{"year":2014,"finding":"A recessive SF-1 (NR5A1) mutation (R103Q) decreases SF-1 transactivation of TLX1, a transcription factor essential for spleen development, without affecting SF-1/SRY co-activation of SOX9. This establishes SF-1 as directly required for spleen development in humans through TLX1 transactivation, and identifies functionally distinct SF-1 activities on different target gene promoters.","method":"Patient mutation identification, transcriptional reporter assays with mutant and wild-type SF-1, target gene promoter analysis","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — natural human mutation with defined functional dissection of target gene activation; single lab but clear mechanistic dissection","pmids":["24905461"],"is_preprint":false},{"year":2018,"finding":"The Mdm2-p53 pathway in ovarian granulosa cells transcriptionally controls SF-1 expression. Mdm2 deficiency in granulosa cells increases p53, which suppresses SF-1 levels, impairing oocyte maturation, ovulation, and fertilization. Mdm2/p53 double deletion restores normal fertility, placing p53 as a negative regulator of SF-1 in granulosa cells.","method":"Conditional Mdm2 knockout mice (two Cre models), Mdm2/p53 double conditional knockout, fertility and ovulation assays, SF-1 expression analysis","journal":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two independent conditional knockout mouse models; genetic epistasis (double KO rescue); single lab","pmids":["30260703"],"is_preprint":false},{"year":2018,"finding":"Insulin increases SF-1 protein and mRNA levels in adrenal cells, partly through suppression of FoxO1. Overexpression of FoxO1 suppresses SF-1 and its steroidogenic target genes. Hyperactivation of insulin signaling in mice increases adrenal SF-1 expression and elevates aldosterone/corticosterone levels; streptozotocin-induced insulin deficiency markedly reduces adrenal SF-1 expression.","method":"In vitro cell treatment with insulin, FoxO1 overexpression, streptozotocin mouse model, insulin-signaling hyperactivation mouse model, qRT-PCR and Western blot","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological and genetic in vivo models without direct mechanistic linkage of insulin signaling to SF-1 promoter; correlative gene expression data; single lab","pmids":["29567944"],"is_preprint":false},{"year":2014,"finding":"Prenatal nicotine exposure reduces histone H3K9 and H3K14 acetylation at the SF-1 promoter via increased HDAC2, reducing SF-1 expression and impairing steroidogenesis in fetal adrenal tissue. Trichostatin A (HDAC inhibitor) reverses the nicotine-mediated inhibition of SF-1 and partial target genes.","method":"Chromatin immunoprecipitation (ChIP for histone acetylation), bisulfite sequencing (DNA methylation), qRT-PCR, Western blot, in vitro cell treatment","journal":"Toxicology and applied pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP for histone marks at SF-1 promoter, but mechanism linking HDAC2 to SF-1 is correlative; pharmacological rescue supports but does not establish direct causality; single lab","pmids":["24709674"],"is_preprint":false}],"current_model":"SF1 (ZFM1/ZCCHC25/ZNF162) is a bifunctional nuclear protein that acts both as a pre-mRNA splicing factor and as a transcriptional repressor: as a splicing factor, it binds the intron branchpoint sequence via its KH domain, cooperatively recruits U2AF65 (interaction regulated by PKG phosphorylation at Ser20 and KIS-mediated SPSP phosphorylation that enhances U2AF65 binding), and promotes U2 snRNP recruitment to the spliceosome through SURP-domain interactions with SF3b1 (a UHM-ULM interface defined crystallographically); as a transcriptional co-regulator, it represses activated transcription by binding partners such as EWS/TLS and the RNAPII elongation factor CA150 (via a novel proline-rich motif), and it suppresses β-catenin/TCF-4 transcriptional output; its activity is further regulated by SUMO modification at Lys119, which selectively blocks DNA binding at noncanonical target loci, and by nuclear body sequestration mediated through the lncRNA Gomafu; in vascular smooth muscle cells, cytokine-induced down-regulation of ZFM1/SF1 promotes proliferation and pro-inflammatory gene expression."},"narrative":{"mechanistic_narrative":"The SF1 symbol in this corpus resolves into two distinct, internally coherent protein identities that must be treated separately. As the pre-mRNA splicing factor (ZFM1/ZNF162), SF1 is an essential metazoan factor required to form the early ATP-dependent pre-spliceosomal complex [PMID:1827409, PMID:10606272]. It recognizes the intron branchpoint through its KH domain, which is the major determinant of RNA binding and conserved from yeast to human [PMID:8752089, PMID:9582097]. The region N-terminal to the KH domain mediates cooperative branchpoint–polypyrimidine tract recognition by recruiting U2AF65 through that factor's degenerate C-terminal RRM [PMID:9512519, PMID:9582097], and SF1 then bridges to the U2 snRNP via a conserved SURP-interaction region that promotes A-complex assembly [PMID:26420826]. This U2AF65 interaction is a regulated node: PKG-I phosphorylation at Ser20 inhibits binding and blocks pre-spliceosome assembly, whereas KIS-mediated phosphorylation of the SPSP motif enhances ternary SF1–U2AF65–RNA complex formation [PMID:10449420, PMID:16420481]. SF1 additionally functions as a transcriptional repressor of activated (not basal) transcription through an N-terminal repression domain, acting on EWS/TLS/TAF activation domains and recruiting the elongation factor CA150 via a C-terminal proline-rich motif [PMID:9506990, PMID:9660765, PMID:11604498], and it suppresses β-catenin/TCF-4 transcriptional output with Sf1-null mice dying before E8.5 [PMID:17900258]. Distinctly, the steroidogenic factor SF-1 (NR5A1) is a DNA-binding nuclear receptor that drives gonadal and adrenal developmental programs: it cooperates with SRY/SOX9 at the Sox9 Tesco enhancer to direct male sex determination [PMID:18454134], is activated by Ptx1, Egr-1, and the coactivator PNRC [PMID:10369682, PMID:10082522, PMID:10894149], and its target-gene selectivity is controlled by SUMOylation at Lys119, which blocks DNA binding at noncanonical loci, and at other residues that enhance DAX1-mediated repression of the fetal adrenal enhancer [PMID:18838537, PMID:28893949]. NR5A1 expression is governed by upstream regulators WT1, LHX9, and FOXL2 [PMID:12130543, PMID:24451388, PMID:27888191], and a recessive NR5A1 R103Q mutation impairs TLX1 transactivation to cause defective spleen development in humans [PMID:24905461].","teleology":[{"year":1991,"claim":"Established that a distinct protein factor is biochemically required to build the earliest spliceosomal complex, defining SF1 as a non-snRNP splicing essential factor.","evidence":"Chromatographic fractionation of HeLa nuclear extract and in vitro pre-splicing complex reconstitution","pmids":["1827409"],"confidence":"High","gaps":["Did not identify the RNA target or domain architecture of the factor","Mechanism of action within the complex undefined"]},{"year":1996,"claim":"Identified SF1 molecularly as a single ~75 kDa KH/zinc-knuckle RNA-binding polypeptide, linking the splicing activity to a defined gene product (ZFM1/ZNF162).","evidence":"cDNA isolation, baculovirus expression, RNA binding assays and complex assembly with multiple isoforms","pmids":["8752089"],"confidence":"High","gaps":["Specific RNA element (branchpoint) not yet pinpointed","Protein partners within the complex not defined"]},{"year":1998,"claim":"Resolved how SF1 achieves initial branchpoint recognition by showing cooperative branchpoint–polypyrimidine binding with U2AF65, and mapped the KH domain as the RNA determinant and the N-terminal region as the U2AF65 contact.","evidence":"Cooperative RNA binding assays, domain mapping, human/yeast chimeric constructs and two-hybrid","pmids":["9512519","9582097"],"confidence":"High","gaps":["How recognition transitions to U2 snRNP recruitment unresolved","Regulation of the interaction not addressed"]},{"year":1998,"claim":"Uncovered an unexpected second role: the same protein (ZFM1) is a sequence-specific transcriptional repressor of activated transcription acting on EWS/TLS/TAF activation domains.","evidence":"Yeast two-hybrid, GST pull-down, and Gal4/reporter repression assays in mammalian cells","pmids":["9506990","9660765"],"confidence":"Medium","gaps":["Repression mechanism on endogenous promoters unclear","Relationship between splicing and transcription roles not integrated"]},{"year":1999,"claim":"Demonstrated that the SF1–U2AF65 interaction is a phosphoregulated switch, with PKG-I phosphorylation at Ser20 inhibiting the interaction and blocking pre-spliceosome assembly.","evidence":"In vitro kinase assay, Ser20 mutagenesis, co-IP, spliceosome assembly readout, and cell-based phosphorylation","pmids":["10449420"],"confidence":"High","gaps":["Physiological signaling contexts that trigger PKG phosphorylation undefined","Effect on global splicing not measured"]},{"year":1999,"claim":"Established SF1 as essential for metazoan development and confirmed the KH domain as the conserved functional core across species.","evidence":"C. elegans RNAi lethality and in vitro reconstitution of Drosophila SF1 in HeLa splicing extracts","pmids":["10606272"],"confidence":"High","gaps":["Role of metazoan-specific RS domains unresolved","Tissue-specific requirements not dissected"]},{"year":2001,"claim":"Connected SF1's transcriptional repression to elongation control by mapping a proline-rich motif that recruits the CTD-binding elongation factor CA150.","evidence":"Domain-mapped co-IP and transcription elongation repression reporter assays","pmids":["11604498"],"confidence":"Medium","gaps":["Endogenous genes regulated by SF1–CA150 unknown","In vivo significance not tested"]},{"year":2001,"claim":"Linked ZFM1/SF1 down-regulation to a disease-relevant proliferative phenotype in vascular smooth muscle cells.","evidence":"Antisense knockdown, proliferation assays, and an in vivo atherosclerosis model","pmids":["11748220"],"confidence":"Medium","gaps":["Direct gene targets mediating proliferation not identified","Whether splicing or transcription function drives the phenotype unclear"]},{"year":2006,"claim":"Identified a positive phosphoregulatory input, showing KIS phosphorylation of the SPSP motif enhances U2AF65 binding and ternary complex formation, complementing the inhibitory PKG input.","evidence":"MS phospho-mapping, in vitro kinase assay, UHM-domain mutagenesis, and ternary complex assays","pmids":["16420481"],"confidence":"High","gaps":["Crosstalk between KIS and PKG phosphorylation untested","Cellular conditions regulating KIS activity undefined"]},{"year":2015,"claim":"Defined how SF1 hands the branchpoint complex off to the U2 snRNP, showing a conserved SURP-interaction region recruits U2 snRNP and is required for A-complex assembly.","evidence":"Reciprocal co-IP, yeast two-hybrid, and SF1 depletion/complementation in spliceosome assembly assays","pmids":["26420826"],"confidence":"High","gaps":["Structural basis of the SURP interaction not resolved here","Additional regulatory inputs at this step unknown"]},{"year":2015,"claim":"Expanded the SF1 splicing interactome by identifying PRPF40B as a direct partner that bridges SF1 and U2AF65 and influences alternative splice site selection.","evidence":"Co-IP, yeast two-hybrid, speckle colocalization, splicing reporters, and siRNA knockdown","pmids":["25605964"],"confidence":"Medium","gaps":["Genome-wide splicing dependence on the SF1–PRPF40B axis not mapped","Mechanistic contribution to spliceosome assembly unclear"]},{"year":2018,"claim":"Provided the high-resolution structural mechanism by which a UHM-containing factor (Tat-SF1) engages SF3b1 through a canonical UHM-ULM interface, defining the molecular interface to the U2 snRNP.","evidence":"1.1 Å crystal structure with interface mutagenesis, co-IP, affinity measurements, and transcriptomics","pmids":["30567737"],"confidence":"High","gaps":["Relationship of Tat-SF1 to the branchpoint-binding SF1 not clarified in this corpus","In vivo splicing dependence partially defined"]},{"year":1999,"claim":"Established the steroidogenic factor SF-1 (NR5A1) as a DNA-binding nuclear receptor whose activity is potentiated by direct partner proteins on gonadotrope promoters.","evidence":"GST pull-down, co-IP, and reporter assays mapping Ptx1 and Egr-1 interactions on LHβ/MIS promoters","pmids":["10369682","10082522"],"confidence":"Medium","gaps":["Endogenous ligand status of SF-1 unresolved","Promoter-selective contributions not fully dissected"]},{"year":2000,"claim":"Identified PNRC as a ligand-independent coactivator of SF-1, defining a proline-rich SH3-binding contact mechanism for transcriptional enhancement.","evidence":"Yeast two-hybrid, GST pull-down, co-IP, reporter assays, and domain mutagenesis","pmids":["10894149"],"confidence":"Medium","gaps":["Physiological gene targets of SF-1/PNRC not defined","In vivo relevance untested"]},{"year":2002,"claim":"Placed NR5A1 within the gonadal developmental hierarchy by identifying WT1(-KTS) and LHX9 as direct upstream transcriptional activators of the Sf1 promoter.","evidence":"Promoter binding/transactivation assays and genetic epistasis with gonad-specific knockouts","pmids":["12130543"],"confidence":"High","gaps":["Combinatorial control with repressors not yet integrated","Stage-specific switching not addressed"]},{"year":2008,"claim":"Revealed that SUMOylation at Lys119 selectively silences SF-1 DNA binding at noncanonical target genes, defining a post-translational mechanism for target-gene discrimination.","evidence":"In vitro sumoylation, K119R/K194R mutants, NMR of the LBD, ChIP, and reporter assays","pmids":["18838537"],"confidence":"High","gaps":["Enzymes setting/removing SUMO in specific tissues undefined","Genome-wide SUMO-sensitive target catalog incomplete"]},{"year":2008,"claim":"Showed SF1 (the splicing/transcription factor) acts as a tumor-suppressive component of the β-catenin/TCF-4 complex, with the gene being embryonically essential.","evidence":"Co-IP, reporter and colony-formation assays, gene-trap knockout mice, and a carcinogen-induced tumor model","pmids":["17900258"],"confidence":"Medium","gaps":["Mechanism of β-catenin/TCF-4 repression unresolved","Whether splicing function contributes to tumor suppression unknown"]},{"year":2008,"claim":"Defined cooperative SF-1/SRY action at the Sox9 Tesco enhancer as the molecular trigger of male sex determination, including a SOX9 feedforward loop.","evidence":"ChIP, enhancer mutation, reporter assays, and in vivo sex-reversal genetics","pmids":["18454134"],"confidence":"High","gaps":["Quantitative thresholds for SF-1 occupancy not defined","Other enhancers co-regulated by this complex not mapped"]},{"year":2011,"claim":"Showed Wnt/β-catenin signaling antagonizes SF-1 function by selectively excluding it from the Tesco enhancer without changing its protein levels, establishing locus-selective regulation of SF-1 occupancy.","evidence":"ChIP at Tesco and Cyp11a1, Wnt pathway manipulation in embryonic gonad culture","pmids":["22128028"],"confidence":"Medium","gaps":["Molecular basis of selective enhancer exclusion unknown","Generality across SF-1 targets untested"]},{"year":2012,"claim":"Provided the dosage-sensitive sex-reversal mechanism by showing excess DAX1 reduces SF-1 binding to the Tesco enhancer.","evidence":"Reporter assays, ChIP for SF-1, Dax1-overexpressing transgenic mice, and Sox9 epistasis","pmids":["22294746"],"confidence":"Medium","gaps":["Direct structural basis of DAX1-mediated SF-1 displacement unclear","Locus selectivity of DAX1 antagonism not fully mapped"]},{"year":2014,"claim":"Identified FOXL2 as a direct repressor of Sf1 that antagonizes WT1-KTS activation, defining the ovarian arm of Sf1 transcriptional control.","evidence":"qRT-PCR, reporter assays, in vitro ChIP, binding-site mutagenesis, and Foxl2-null mice","pmids":["24451388"],"confidence":"Medium","gaps":["Dynamic balance between FOXL2 and WT1 in vivo not quantified","Downstream consequences of Sf1 derepression incomplete"]},{"year":2014,"claim":"Demonstrated promoter-selective SF-1 functions in humans by showing the R103Q mutation impairs TLX1 transactivation (and spleen development) while sparing SOX9 co-activation.","evidence":"Patient mutation analysis and wild-type/mutant SF-1 reporter assays on distinct target promoters","pmids":["24905461"],"confidence":"Medium","gaps":["Structural basis of target-selective loss not resolved","Full spectrum of R103Q-affected targets unknown"]},{"year":2016,"claim":"Established WT1 as also a repressive controller of Sf1 timing, showing premature Sf1 upregulation upon Wt1 loss redirects somatic cells toward a steroidogenic rather than supporting fate.","evidence":"Temporal conditional Wt1 knockout, promoter binding with binding-site mutagenesis, and lineage analysis","pmids":["27888191"],"confidence":"High","gaps":["Switch between WT1 activator and repressor roles not mechanistically defined","Cofactors mediating WT1 repression unknown"]},{"year":2017,"claim":"Refined SF-1 SUMO biology by showing SUMOylation enhances DAX1 recruitment to repress the fetal adrenal enhancer, controlling postnatal adrenal X-zone regression.","evidence":"SUMOylation-deficient knock-in mice, Dax1 knockout mice, FAdE-lacZ reporter mice, and interaction assays","pmids":["28893949"],"confidence":"High","gaps":["How SUMO promotes DAX1 binding mechanistically unclear","Other SUMO-dependent corepressors not identified"]},{"year":2018,"claim":"Identified the Mdm2-p53 axis as a transcriptional controller of SF-1 in granulosa cells required for ovulation and fertility.","evidence":"Conditional Mdm2 knockouts, Mdm2/p53 double knockout rescue, and fertility/SF-1 expression analysis","pmids":["30260703"],"confidence":"Medium","gaps":["Whether p53 acts directly on the Sf1 promoter not established","Direct steroidogenic targets affected not fully mapped"]},{"year":2018,"claim":"Linked metabolic insulin signaling to adrenal SF-1 levels via FoxO1 suppression, connecting SF-1 to systemic energy state.","evidence":"Insulin treatment, FoxO1 overexpression, and insulin-deficient/hyperactive mouse models","pmids":["29567944"],"confidence":"Low","gaps":["No direct mechanistic linkage of insulin signaling to the Sf1 promoter (correlative expression data)","FoxO1 binding to Sf1 regulatory regions not demonstrated"]},{"year":2014,"claim":"Implicated chromatin-level control of SF-1, showing prenatal nicotine reduces SF-1 promoter histone acetylation via HDAC2 to impair steroidogenesis.","evidence":"ChIP for histone marks, bisulfite sequencing, qRT-PCR, and HDAC-inhibitor rescue","pmids":["24709674"],"confidence":"Low","gaps":["HDAC2-to-SF-1 link is correlative, not causally established","Direct recruitment of HDAC2 to the Sf1 promoter not shown"]},{"year":null,"claim":"It remains unresolved within this corpus whether the branchpoint-binding splicing factor SF1 (ZFM1) and the steroidogenic nuclear receptor SF-1 (NR5A1) represent one protein with dual roles or two distinct gene products conflated by symbol, and how their respective regulatory networks intersect.","evidence":"","pmids":[],"confidence":"Low","gaps":["No timeline discovery reconciles the KH/U2AF65 splicing identity with the DNA-binding NR5A1 nuclear-receptor identity","Cross-talk between splicing and transcriptional/steroidogenic functions not directly tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,2,3,12]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,6,14,24]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[15,24,28]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,9,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[18,20,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,15,24]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[10,12]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,6,7,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[21,24,23]}],"complexes":["pre-spliceosome (E complex)","U2 snRNP-associated branchpoint complex","beta-catenin/TCF-4 transcriptional complex"],"partners":["U2AF65","SF3B1","SF3B4","PRPF40B","CA150","EWS","DAX1","SRY"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13285","full_name":"Steroidogenic factor 1","aliases":["Adrenal 4-binding protein","Fushi tarazu factor homolog 1","Nuclear receptor subfamily 5 group A member 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Essential for sexual differentiation and formation of the primary steroidogenic tissues (PubMed:27378692). Binds to the Ad4 site found in the promoter region of steroidogenic P450 genes such as CYP11A, CYP11B and CYP21B. Also regulates the AMH/Muellerian inhibiting substance gene as well as the AHCH and STAR genes. 5'-YCAAGGYC-3' and 5'-RRAGGTCA-3' are the consensus sequences for the recognition by NR5A1 (PubMed:27378692). The SFPQ-NONO-NR5A1 complex binds to the CYP17 promoter and regulates basal and cAMP-dependent transcriptional activity. Binds phosphatidylcholine (By similarity). Binds phospholipids with a phosphatidylinositol (PI) headgroup, in particular PI(3,4)P2 and PI(3,4,5)P3. Activated by the phosphorylation of NR5A1 by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q13285/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SF1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CAPZB","stoichiometry":0.2},{"gene":"SSB","stoichiometry":0.2},{"gene":"U2AF2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SF1","total_profiled":1310},"omim":[{"mim_id":"621019","title":"PRE-mRNA-PROCESSING FACTOR 40 HOMOLOG B; PRPF40B","url":"https://www.omim.org/entry/621019"},{"mim_id":"620472","title":"TRAFFICKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2B; TRAPPC2B","url":"https://www.omim.org/entry/620472"},{"mim_id":"620006","title":"RAD54-LIKE 2; RAD54L2","url":"https://www.omim.org/entry/620006"},{"mim_id":"614732","title":"INTRAUTERINE GROWTH RETARDATION, METAPHYSEAL DYSPLASIA, ADRENAL HYPOPLASIA CONGENITA, AND GENITAL ANOMALIES; IMAGE","url":"https://www.omim.org/entry/614732"},{"mim_id":"613743","title":"ADRENAL INSUFFICIENCY, CONGENITAL, WITH 46,XY SEX REVERSAL, PARTIAL OR COMPLETE","url":"https://www.omim.org/entry/613743"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SF1"},"hgnc":{"alias_symbol":["ZFM1","ZCCHC25","BBP"],"prev_symbol":["ZNF162"]},"alphafold":{"accession":"Q13285","domains":[{"cath_id":"3.30.50.10","chopping":"21-113","consensus_level":"high","plddt":89.3052,"start":21,"end":113},{"cath_id":"1.10.565.10","chopping":"224-248_257-458","consensus_level":"high","plddt":91.9197,"start":224,"end":458}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13285","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13285-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13285-F1-predicted_aligned_error_v6.png","plddt_mean":77.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SF1","jax_strain_url":"https://www.jax.org/strain/search?query=SF1"},"sequence":{"accession":"Q13285","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13285.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13285/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13285"}},"corpus_meta":[{"pmid":"20456941","id":"PMC_20456941","title":"SF1 and SF2 helicases: family matters.","date":"2010","source":"Current opinion in structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/20456941","citation_count":766,"is_preprint":false},{"pmid":"18454134","id":"PMC_18454134","title":"Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18454134","citation_count":712,"is_preprint":false},{"pmid":"9514159","id":"PMC_9514159","title":"The pan-pituitary activator of transcription, Ptx1 (pituitary homeobox 1), acts in synergy with SF-1 and Pit1 and is an upstream regulator of the Lim-homeodomain gene Lim3/Lhx3.","date":"1998","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/9514159","citation_count":240,"is_preprint":false},{"pmid":"10082522","id":"PMC_10082522","title":"Egr-1 is a downstream effector of GnRH and synergizes by direct interaction with Ptx1 and SF-1 to enhance luteinizing hormone beta gene transcription.","date":"1999","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10082522","citation_count":227,"is_preprint":false},{"pmid":"12130543","id":"PMC_12130543","title":"The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1.","date":"2002","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/12130543","citation_count":214,"is_preprint":false},{"pmid":"9512519","id":"PMC_9512519","title":"A cooperative interaction between U2AF65 and mBBP/SF1 facilitates branchpoint region recognition.","date":"1998","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9512519","citation_count":213,"is_preprint":false},{"pmid":"11124111","id":"PMC_11124111","title":"Steroidogenic factor 1 (SF1) is essential for pituitary gonadotrope function.","date":"2001","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11124111","citation_count":181,"is_preprint":false},{"pmid":"26303087","id":"PMC_26303087","title":"DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease.","date":"2015","source":"Best practice & research. 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It contains a KH domain and zinc knuckle required for RNA binding and binds directly to RNA with preference for G- and U-rich sequences. Multiple SF1 isoforms expressed via baculovirus showed comparable activities in pre-splicing complex assembly.\",\n      \"method\": \"cDNA isolation, baculovirus expression, RNA binding assays, in vitro splicing complex assembly\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical assays (RNA binding, complex assembly), multiple isoforms tested, replicated across constructs in one rigorous study\",\n      \"pmids\": [\"8752089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"SF1 (splicing factor 1) is an essential protein factor required for the formation of the pre-splicing complex (early ATP-dependent spliceosomal complex), functioning together with SF3 and U2AF, and is essential for production of spliced RNA.\",\n      \"method\": \"Chromatographic fractionation of HeLa nuclear extracts, in vitro splicing assays, pre-splicing complex assembly\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with fractionated components; requirement established by depletion and complementation\",\n      \"pmids\": [\"1827409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Mammalian SF1 (mBBP/SF1) binds specifically to the branchpoint sequence and interacts with U2AF65, which binds the adjacent polypyrimidine tract. This protein-protein interaction promotes cooperative binding to a branchpoint sequence-polypyrimidine tract RNA, contributing to initial branchpoint sequence recognition. The third RBD (degenerate RRM) of U2AF65 is essential for the SF1 interaction.\",\n      \"method\": \"RNA binding assays, protein-protein interaction assays, cooperative binding experiments, domain mapping\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical reconstitution of cooperative RNA binding, domain-mapping of the interaction, multiple orthogonal assays\",\n      \"pmids\": [\"9512519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The KH domain of human SF1 is the major determinant for RNA binding and is essential for spliceosome assembly. The region N-terminal to the KH domain mediates the interaction with U2AF65. Yeast SF1 similarly interacts with Mud2p (the yeast U2AF65 homologue) via its conserved C-terminal degenerate RRM. The KH domain function is conserved between human and yeast SF1.\",\n      \"method\": \"Domain deletion analysis, chimeric construct analysis, yeast two-hybrid, in vitro spliceosome assembly\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple domain-mapping experiments and chimeric constructs in both human and yeast systems, in vitro assembly assays\",\n      \"pmids\": [\"9582097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SF1 (splicing factor 1) is phosphorylated by cGMP-dependent protein kinase I (PKG-I) at Ser20. This phosphorylation inhibits the SF1-U2AF65 interaction and blocks pre-spliceosome assembly. Mutation of Ser20 to Ala or Thr also inhibits the interaction with U2AF65, indicating Ser20 is essential for binding. Phosphorylation of SF1 on Ser20 occurs in cultured neuronal cells and is increased by cGMP analogue treatment.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, co-immunoprecipitation, pre-spliceosome assembly assay, cell-based phosphorylation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay with mutagenesis, functional spliceosome assembly readout, and cell-based validation; multiple orthogonal methods\",\n      \"pmids\": [\"10449420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ZFM1 (identical to splicing factor SF1) functions as a transcriptional repressor. Its N-terminal 137 amino acids contain a repression domain. ZFM1 interacts with the transcription activation domain of SSAP (a sea urchin transcription factor) and represses Gal4-GQC-mediated transcription; only activated, not basal, transcription is affected.\",\n      \"method\": \"Yeast two-hybrid, functional transcription repression assays in mammalian cells, Gal4 fusion assays, domain mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional reporter assays in mammalian cells; single lab but multiple assays\",\n      \"pmids\": [\"9506990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"ZFM1/SF1 interacts with the EWS transcriptional activation domain (NTD) via a 37 amino acid region. Overexpression of ZFM1 in HepG2 cells represses EWS-NTD-driven transcription. ZFM1 also interacts with TLS and hTAFII68, proteins homologous to EWS. This suggests ZFM1 negatively modulates transcription coordinated by EWS/TLS/TAF cofactors.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, reporter gene assays in HepG2 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — GST pull-down plus yeast two-hybrid plus functional repression assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"9660765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The transcription elongation factor CA150 directly binds to SF1 through its WW1 and WW2 domains interacting with a novel proline-rich motif in the C-terminal half of SF1. This interaction is required for efficient CA150-mediated repression of transcription elongation. CA150 also binds to the phosphorylated CTD of RNAPII via its FF repeats, suggesting SF1 targets the nascent transcript to recruit CA150.\",\n      \"method\": \"Protein-protein interaction mapping, co-immunoprecipitation, transcription repression reporter assays, domain deletion analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapped by domain analysis plus functional repression assays; single lab, multiple methods\",\n      \"pmids\": [\"11604498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SF1 is highly phosphorylated in mammalian cells on two serines within an SPSP motif (at the junction between its U2AF65 and RNA binding domains) by the kinase KIS. KIS interacts with SF1 via its UHM domain, which is required for efficient SPSP phosphorylation. SPSP phosphorylation by KIS increases SF1 binding to U2AF65 and enhances formation of the ternary SF1-U2AF65-RNA complex.\",\n      \"method\": \"Mass spectrometry phosphorylation mapping, in vitro kinase assay, protein-protein interaction assays, domain mutagenesis, ternary complex formation assay\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay with defined substrate site, domain mapping, functional ternary complex assay; multiple orthogonal methods in one study\",\n      \"pmids\": [\"16420481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SF1 interacts with SURP domain-containing U2 snRNP proteins (SAP49/SF3b4 and SF3b1-related factors) via a short evolutionarily conserved region. Co-immunoprecipitation from HeLa extracts found nearly all U2 snRNP proteins associated with SF1. Depletion of SF1 reduced A complex (spliceosome) formation, rescued by recombinant SF1 containing the SURP-interaction domain but only partially by SF1 lacking this domain. This shows SF1 can recruit U2 snRNP to the spliceosome during E complex formation.\",\n      \"method\": \"Co-immunoprecipitation from HeLa extracts, yeast two-hybrid, SF1 depletion and complementation, spliceosomal complex assembly assay\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — functional depletion/rescue assays combined with reciprocal co-IP and yeast two-hybrid; multiple orthogonal methods in one study\",\n      \"pmids\": [\"26420826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PRPF40B directly interacts with SF1 and associates with U2AF65. PRPF40B colocalizes with SF1 and U2AF65 in nuclear speckles. PRPF40B modulates alternative splice site selection and depletion of PRPF40B increases Fas/CD95 receptor levels and cell apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, colocalization by immunofluorescence, alternative splicing reporter assays, siRNA knockdown\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction established by co-IP and yeast two-hybrid; functional consequences via splicing reporter and knockdown; single lab\",\n      \"pmids\": [\"25605964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Drosophila SF1 (DmSF1) and C. elegans SF1 (CeSF1) contain N-terminal RS domains enriched in Ser, Arg, Lys, and Asp residues, unlike their yeast and mammalian counterparts. DmSF1 lacking its N-terminus is functional in prespliceosome formation in a HeLa splicing system, showing the KH domain function is conserved. CeSF1 is essential for viability (injection of dsRNA causes embryonic lethality in C. elegans), establishing SF1 as essential for metazoan development.\",\n      \"method\": \"cDNA isolation, RNAi (C. elegans), in vitro splicing reconstitution in HeLa extracts, protein interaction assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — genetic loss-of-function (lethality) in C. elegans combined with in vitro functional reconstitution; two orthogonal approaches\",\n      \"pmids\": [\"10606272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SF1 and the RNA-binding protein Celf3 co-localize in novel nuclear bodies (CS bodies) in neuroblastoma Neuro2A cells. The lncRNA Gomafu binds both SF1 and Celf3 but forms distinct nuclear bodies separate from CS bodies, suggesting Gomafu indirectly modulates SF1 function by sequestering it into separate compartments.\",\n      \"method\": \"Cross-link RNA precipitation, knockdown, immunofluorescence colocalization, nuclear body imaging\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct RNA-protein binding confirmed by CLIP; colocalization by imaging; functional consequence inferred; single lab\",\n      \"pmids\": [\"25145264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Down-regulation of ZFM1/SF1 (splicing factor 1) by IL-1β and TNF-α in vascular smooth muscle cells promotes cell proliferation and expression of pro-inflammatory gene products (MCP-1, VCAM-1). Antisense oligonucleotide suppression of ZFM1 protein mimics cytokine-stimulated SMC proliferation. In an atherosclerosis mouse model, ZFM1 abundance was decreased in proliferating arterial SMC.\",\n      \"method\": \"Suppression subtractive hybridization, antisense oligonucleotides, cell proliferation assay, in vivo atherosclerosis model, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antisense knockdown with defined proliferation phenotype, corroborated by in vivo model; single lab, multiple methods\",\n      \"pmids\": [\"11748220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SF1 (splicing factor 1) was identified as a novel component of the β-catenin/TCF-4 transcriptional complex. Overexpression of SF1 inhibited the transcriptional activity of this complex and markedly suppressed β-catenin-evoked colony formation in HEK293 cells. Homozygous SF1 knockout mice die before E8.5; heterozygous Sf1+/- mice are viable but more susceptible to azoxymethane-induced colon tumorigenesis.\",\n      \"method\": \"Co-immunoprecipitation (complex identification), reporter assay, colony formation assay, gene trap knockout mice, carcinogen-induced tumor model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex membership established by co-IP; functional consequence in vitro (reporter + colony assay) and in vivo (knockout + carcinogen model); single lab\",\n      \"pmids\": [\"17900258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUMO modification of SF-1 (NR5A1) at Lys119 (adjacent to the DNA-binding domain) results in a marked and selective loss of DNA binding to noncanonical SF-1 target genes (e.g. inhibin-α). DNA binding and sumoylation of Lys119 are mutually exclusive. Sumoylation at Lys194 (adjacent to the LBD) modestly reduces Ser203 phosphorylation but does not greatly impair coregulator recruitment or conformation. The K119R mutant is selectively recruited to SUMO-sensitive sites in the endogenous inhibin-α promoter, leading to increased transcription.\",\n      \"method\": \"In vitro sumoylation, site-directed mutagenesis (K119R, K194R), NMR structural analysis of sumoylated LBD, chromatin immunoprecipitation, transcriptional reporter assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro sumoylation combined with structural (NMR), ChIP, and functional reporter assays; multiple orthogonal methods in one study\",\n      \"pmids\": [\"18838537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SF1 SUMOylation increases binding of DAX1 to SF1 (without directly influencing SF1 DNA binding), thereby enhancing transcriptional repression of the fetal adrenal enhancer (FAdE). SUMOylation-deficient SF1 mice and Dax1 knockout mice both show delayed regression of the postnatal fetal adrenal cortex (X-zone) and prolonged FAdE expression, defining a cooperative repressor function.\",\n      \"method\": \"SUMOylation-deficient knock-in mice, Dax1 knockout mice, reporter mouse (FAdE-lacZ), in vitro protein-protein interaction assays\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic models (two independent mouse lines) with defined phenotype, supported by in vitro interaction data; two labs' approaches converge\",\n      \"pmids\": [\"28893949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Tat-SF1 contains a U2AF homology motif (UHM) protein-protein interaction module (determined by 1.1 Å crystal structure). Tat-SF1 preferentially and directly binds the SF3b1 subunit of the U2 snRNP via a canonical UHM-ULM interface (Tat-SF1 binding pocket for SF3b1 Trp338). SF3b1 regulates Tat-SF1 protein levels, and these two factors influence expression of overlapping transcripts.\",\n      \"method\": \"Crystal structure (1.1 Å, 1.9 Å, 2.1 Å resolution), co-immunoprecipitation, binding affinity measurements, siRNA knockdown, transcriptomics\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures of the complex with mutagenic validation of the interface; orthogonal functional assays; rigorous study\",\n      \"pmids\": [\"30567737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ptx1 interacts directly with SF-1 (NR5A1/steroidogenic factor 1) through its C-terminus binding the N-terminal half of SF-1. This interaction requires SF-1 DNA binding and results in transcriptional enhancement equivalent to a constitutively active SF-1 mutant, mimicking the effect of a putative SF-1 ligand. This synergism is observed on the LH-beta and MIS promoters.\",\n      \"method\": \"GST pull-down, co-immunoprecipitation, transcriptional reporter assays, constitutively active SF-1 mutant comparison, domain mapping\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct physical interaction established by GST pulldown plus functional transcription assays; single lab, two orthogonal methods\",\n      \"pmids\": [\"10369682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Egr-1 interacts directly with both Ptx1 and SF-1, and these interactions enhance Ptx1- and SF-1-induced LHβ transcription. GnRH stimulates Egr-1 (but not Ptx1 or SF-1) expression via the PKC pathway, establishing Egr-1 as a transcriptional mediator of GnRH signaling that converges on SF-1 activity.\",\n      \"method\": \"GST pull-down (direct interaction), co-transfection reporter assays, PKC activation studies, GnRH stimulation experiments\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction by GST pulldown combined with functional reporter assays and GnRH stimulation; single lab\",\n      \"pmids\": [\"10082522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PNRC (proline-rich nuclear receptor coregulatory protein) interacts directly with SF1 (steroidogenic factor 1) in a ligand-independent manner via a 23-amino acid C-terminal sequence containing an SH3-binding motif (SDPPSPSP), with the two conserved prolines required for interaction. PNRC functions as a coactivator to enhance SF1-mediated transcriptional activation. Direct contact between PNRC and SF1 was confirmed by GST pull-down.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, transcriptional reporter assays, domain mutagenesis\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction confirmed by GST pulldown; functional activation assays; domain mutants; single lab\",\n      \"pmids\": [\"10894149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"WT1 (specifically the -KTS isoform) directly binds to and transactivates the Sf1 promoter, establishing WT1 as a direct upstream activator of SF1 expression. LHX9 also functions as a direct activator of the Sf1 gene. Genetic experiments placed Wt1 and Lhx9 upstream of Sf1 in the gonadal development pathway.\",\n      \"method\": \"Biochemical binding assays, transcriptional reporter assays, genetic epistasis (gonad-specific knockout models), promoter analysis\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding and transactivation combined with genetic epistasis; two independent upstream regulators identified; replicated approaches\",\n      \"pmids\": [\"12130543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FOXL2 transcriptionally represses Sf1 expression by directly binding a conserved FOXL2 binding site in the Sf1 proximal promoter and antagonizing WT1-KTS-mediated activation. Mutation of the FOXL2 binding site abolishes repression in reporter assays. In Foxl2-null mice, Sf1 expression is increased ~2-fold in XX fetal gonads.\",\n      \"method\": \"Quantitative RT-PCR, reporter assays, in vitro ChIP, site-directed mutagenesis, Foxl2-null mouse model\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, mutant reporter assay, and in vivo mouse model; single lab, multiple methods\",\n      \"pmids\": [\"24451388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"WT1 represses Sf1 expression by directly binding to the Sf1 promoter region. When WT1 binding sites are mutated, the repressive function is abolished. Loss of Wt1 before sex determination causes upregulation of Sf1, leading to differentiation of somatic cells into steroidogenic cells instead of supporting (Sertoli/granulosa) cells.\",\n      \"method\": \"Conditional Wt1 knockout mice (temporal deletion), promoter binding assay, site-directed mutagenesis of WT1 binding sites, histological and gene expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct promoter binding with mutagenesis confirmation, combined with in vivo conditional knockout with clear cell lineage phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"27888191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SRY binds to multiple elements within a Sox9 gonad-specific enhancer (Tesco) together with SF1 (NR5A1). SF1 and SRY cooperatively upregulate Sox9 expression; SOX9 subsequently also binds the same enhancer along with SF1 to maintain its own expression after SRY expression ceases (feedforward loop). Mutation and sex-reversal studies confirmed that cooperative SF1/SRY binding to the enhancer is required for male sex determination.\",\n      \"method\": \"ChIP, enhancer mutation studies, co-transfection reporter assays, sex-reversal genetic experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP binding data, functional enhancer mutations, and in vivo sex-reversal genetic validation; multiple orthogonal methods; high-impact study\",\n      \"pmids\": [\"18454134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ectopic activation of Wnt/β-catenin signaling in male gonads reduces SF1 binding to the Tesco (Sox9 testis) enhancer without altering SF1 mRNA or protein levels, abolishing Sox9 expression. SF1 binding to the Cyp11a1 promoter (a Leydig cell target) was not affected. This demonstrates that Wnt/β-catenin signaling selectively prevents SF1 from accessing specific enhancers.\",\n      \"method\": \"ChIP for SF1 at Tesco enhancer and Cyp11a1 promoter, Wnt/β-catenin pathway activation/inhibition, embryonic gonad culture, gene expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating selective loss of SF1 binding at specific loci; supported by gene expression data; single lab\",\n      \"pmids\": [\"22128028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Excess DAX1 antagonizes SF1-, SF1/SRY-, and SF1/SOX9-mediated activation of the Sox9 testis enhancer (Tesco) by reducing SF1 binding to Tesco. This provides the molecular mechanism for dosage-sensitive sex reversal: increased DAX1 impairs SF1-mediated Sox9 activation.\",\n      \"method\": \"Reporter assays in cultured cells, ChIP for SF1 at Tesco, transgenic mice overexpressing Dax1, genetic epistasis with Sox9 heterozygotes\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP showing reduced SF1 binding, reporter assays with dose-response, and in vivo transgenic validation; single lab\",\n      \"pmids\": [\"22294746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"GPR30/GPER activation (by tamoxifen analogue STX) increases cellular pools of phosphatidylinositol (3,4,5) triphosphate via PI3K signaling, which activates SF-1 (NR5A1) transcription, promotes endometrial cell proliferation, and induces the SF-1 target gene aromatase. This establishes a GPR30→PI3K→SF-1 signaling axis.\",\n      \"method\": \"PI3K/MAPK pathway activation assays, SF-1 transcription reporter assays, cell proliferation assays, siRNA for GPR30, PI3P measurement\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological activation with GPR30-specific compound, siRNA knockdown validation, functional proliferation assay; single lab\",\n      \"pmids\": [\"19549922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A recessive SF-1 (NR5A1) mutation (R103Q) decreases SF-1 transactivation of TLX1, a transcription factor essential for spleen development, without affecting SF-1/SRY co-activation of SOX9. This establishes SF-1 as directly required for spleen development in humans through TLX1 transactivation, and identifies functionally distinct SF-1 activities on different target gene promoters.\",\n      \"method\": \"Patient mutation identification, transcriptional reporter assays with mutant and wild-type SF-1, target gene promoter analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural human mutation with defined functional dissection of target gene activation; single lab but clear mechanistic dissection\",\n      \"pmids\": [\"24905461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The Mdm2-p53 pathway in ovarian granulosa cells transcriptionally controls SF-1 expression. Mdm2 deficiency in granulosa cells increases p53, which suppresses SF-1 levels, impairing oocyte maturation, ovulation, and fertilization. Mdm2/p53 double deletion restores normal fertility, placing p53 as a negative regulator of SF-1 in granulosa cells.\",\n      \"method\": \"Conditional Mdm2 knockout mice (two Cre models), Mdm2/p53 double conditional knockout, fertility and ovulation assays, SF-1 expression analysis\",\n      \"journal\": \"FASEB journal : official publication of the Federation of American Societies for Experimental Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent conditional knockout mouse models; genetic epistasis (double KO rescue); single lab\",\n      \"pmids\": [\"30260703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Insulin increases SF-1 protein and mRNA levels in adrenal cells, partly through suppression of FoxO1. Overexpression of FoxO1 suppresses SF-1 and its steroidogenic target genes. Hyperactivation of insulin signaling in mice increases adrenal SF-1 expression and elevates aldosterone/corticosterone levels; streptozotocin-induced insulin deficiency markedly reduces adrenal SF-1 expression.\",\n      \"method\": \"In vitro cell treatment with insulin, FoxO1 overexpression, streptozotocin mouse model, insulin-signaling hyperactivation mouse model, qRT-PCR and Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological and genetic in vivo models without direct mechanistic linkage of insulin signaling to SF-1 promoter; correlative gene expression data; single lab\",\n      \"pmids\": [\"29567944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Prenatal nicotine exposure reduces histone H3K9 and H3K14 acetylation at the SF-1 promoter via increased HDAC2, reducing SF-1 expression and impairing steroidogenesis in fetal adrenal tissue. Trichostatin A (HDAC inhibitor) reverses the nicotine-mediated inhibition of SF-1 and partial target genes.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP for histone acetylation), bisulfite sequencing (DNA methylation), qRT-PCR, Western blot, in vitro cell treatment\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP for histone marks at SF-1 promoter, but mechanism linking HDAC2 to SF-1 is correlative; pharmacological rescue supports but does not establish direct causality; single lab\",\n      \"pmids\": [\"24709674\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SF1 (ZFM1/ZCCHC25/ZNF162) is a bifunctional nuclear protein that acts both as a pre-mRNA splicing factor and as a transcriptional repressor: as a splicing factor, it binds the intron branchpoint sequence via its KH domain, cooperatively recruits U2AF65 (interaction regulated by PKG phosphorylation at Ser20 and KIS-mediated SPSP phosphorylation that enhances U2AF65 binding), and promotes U2 snRNP recruitment to the spliceosome through SURP-domain interactions with SF3b1 (a UHM-ULM interface defined crystallographically); as a transcriptional co-regulator, it represses activated transcription by binding partners such as EWS/TLS and the RNAPII elongation factor CA150 (via a novel proline-rich motif), and it suppresses β-catenin/TCF-4 transcriptional output; its activity is further regulated by SUMO modification at Lys119, which selectively blocks DNA binding at noncanonical target loci, and by nuclear body sequestration mediated through the lncRNA Gomafu; in vascular smooth muscle cells, cytokine-induced down-regulation of ZFM1/SF1 promotes proliferation and pro-inflammatory gene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The SF1 symbol in this corpus resolves into two distinct, internally coherent protein identities that must be treated separately. As the pre-mRNA splicing factor (ZFM1/ZNF162), SF1 is an essential metazoan factor required to form the early ATP-dependent pre-spliceosomal complex [#1, #11]. It recognizes the intron branchpoint through its KH domain, which is the major determinant of RNA binding and conserved from yeast to human [#0, #3]. The region N-terminal to the KH domain mediates cooperative branchpoint–polypyrimidine tract recognition by recruiting U2AF65 through that factor's degenerate C-terminal RRM [#2, #3], and SF1 then bridges to the U2 snRNP via a conserved SURP-interaction region that promotes A-complex assembly [#9]. This U2AF65 interaction is a regulated node: PKG-I phosphorylation at Ser20 inhibits binding and blocks pre-spliceosome assembly, whereas KIS-mediated phosphorylation of the SPSP motif enhances ternary SF1–U2AF65–RNA complex formation [#4, #8]. SF1 additionally functions as a transcriptional repressor of activated (not basal) transcription through an N-terminal repression domain, acting on EWS/TLS/TAF activation domains and recruiting the elongation factor CA150 via a C-terminal proline-rich motif [#5, #6, #7], and it suppresses β-catenin/TCF-4 transcriptional output with Sf1-null mice dying before E8.5 [#14]. Distinctly, the steroidogenic factor SF-1 (NR5A1) is a DNA-binding nuclear receptor that drives gonadal and adrenal developmental programs: it cooperates with SRY/SOX9 at the Sox9 Tesco enhancer to direct male sex determination [#24], is activated by Ptx1, Egr-1, and the coactivator PNRC [#18, #19, #20], and its target-gene selectivity is controlled by SUMOylation at Lys119, which blocks DNA binding at noncanonical loci, and at other residues that enhance DAX1-mediated repression of the fetal adrenal enhancer [#15, #16]. NR5A1 expression is governed by upstream regulators WT1, LHX9, and FOXL2 [#21, #22, #23], and a recessive NR5A1 R103Q mutation impairs TLX1 transactivation to cause defective spleen development in humans [#28].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that a distinct protein factor is biochemically required to build the earliest spliceosomal complex, defining SF1 as a non-snRNP splicing essential factor.\",\n      \"evidence\": \"Chromatographic fractionation of HeLa nuclear extract and in vitro pre-splicing complex reconstitution\",\n      \"pmids\": [\"1827409\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the RNA target or domain architecture of the factor\", \"Mechanism of action within the complex undefined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified SF1 molecularly as a single ~75 kDa KH/zinc-knuckle RNA-binding polypeptide, linking the splicing activity to a defined gene product (ZFM1/ZNF162).\",\n      \"evidence\": \"cDNA isolation, baculovirus expression, RNA binding assays and complex assembly with multiple isoforms\",\n      \"pmids\": [\"8752089\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific RNA element (branchpoint) not yet pinpointed\", \"Protein partners within the complex not defined\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Resolved how SF1 achieves initial branchpoint recognition by showing cooperative branchpoint–polypyrimidine binding with U2AF65, and mapped the KH domain as the RNA determinant and the N-terminal region as the U2AF65 contact.\",\n      \"evidence\": \"Cooperative RNA binding assays, domain mapping, human/yeast chimeric constructs and two-hybrid\",\n      \"pmids\": [\"9512519\", \"9582097\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How recognition transitions to U2 snRNP recruitment unresolved\", \"Regulation of the interaction not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Uncovered an unexpected second role: the same protein (ZFM1) is a sequence-specific transcriptional repressor of activated transcription acting on EWS/TLS/TAF activation domains.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and Gal4/reporter repression assays in mammalian cells\",\n      \"pmids\": [\"9506990\", \"9660765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Repression mechanism on endogenous promoters unclear\", \"Relationship between splicing and transcription roles not integrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrated that the SF1–U2AF65 interaction is a phosphoregulated switch, with PKG-I phosphorylation at Ser20 inhibiting the interaction and blocking pre-spliceosome assembly.\",\n      \"evidence\": \"In vitro kinase assay, Ser20 mutagenesis, co-IP, spliceosome assembly readout, and cell-based phosphorylation\",\n      \"pmids\": [\"10449420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signaling contexts that trigger PKG phosphorylation undefined\", \"Effect on global splicing not measured\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established SF1 as essential for metazoan development and confirmed the KH domain as the conserved functional core across species.\",\n      \"evidence\": \"C. elegans RNAi lethality and in vitro reconstitution of Drosophila SF1 in HeLa splicing extracts\",\n      \"pmids\": [\"10606272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Role of metazoan-specific RS domains unresolved\", \"Tissue-specific requirements not dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Connected SF1's transcriptional repression to elongation control by mapping a proline-rich motif that recruits the CTD-binding elongation factor CA150.\",\n      \"evidence\": \"Domain-mapped co-IP and transcription elongation repression reporter assays\",\n      \"pmids\": [\"11604498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous genes regulated by SF1–CA150 unknown\", \"In vivo significance not tested\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked ZFM1/SF1 down-regulation to a disease-relevant proliferative phenotype in vascular smooth muscle cells.\",\n      \"evidence\": \"Antisense knockdown, proliferation assays, and an in vivo atherosclerosis model\",\n      \"pmids\": [\"11748220\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct gene targets mediating proliferation not identified\", \"Whether splicing or transcription function drives the phenotype unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified a positive phosphoregulatory input, showing KIS phosphorylation of the SPSP motif enhances U2AF65 binding and ternary complex formation, complementing the inhibitory PKG input.\",\n      \"evidence\": \"MS phospho-mapping, in vitro kinase assay, UHM-domain mutagenesis, and ternary complex assays\",\n      \"pmids\": [\"16420481\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between KIS and PKG phosphorylation untested\", \"Cellular conditions regulating KIS activity undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined how SF1 hands the branchpoint complex off to the U2 snRNP, showing a conserved SURP-interaction region recruits U2 snRNP and is required for A-complex assembly.\",\n      \"evidence\": \"Reciprocal co-IP, yeast two-hybrid, and SF1 depletion/complementation in spliceosome assembly assays\",\n      \"pmids\": [\"26420826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the SURP interaction not resolved here\", \"Additional regulatory inputs at this step unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Expanded the SF1 splicing interactome by identifying PRPF40B as a direct partner that bridges SF1 and U2AF65 and influences alternative splice site selection.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, speckle colocalization, splicing reporters, and siRNA knockdown\",\n      \"pmids\": [\"25605964\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide splicing dependence on the SF1–PRPF40B axis not mapped\", \"Mechanistic contribution to spliceosome assembly unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided the high-resolution structural mechanism by which a UHM-containing factor (Tat-SF1) engages SF3b1 through a canonical UHM-ULM interface, defining the molecular interface to the U2 snRNP.\",\n      \"evidence\": \"1.1 Å crystal structure with interface mutagenesis, co-IP, affinity measurements, and transcriptomics\",\n      \"pmids\": [\"30567737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of Tat-SF1 to the branchpoint-binding SF1 not clarified in this corpus\", \"In vivo splicing dependence partially defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Established the steroidogenic factor SF-1 (NR5A1) as a DNA-binding nuclear receptor whose activity is potentiated by direct partner proteins on gonadotrope promoters.\",\n      \"evidence\": \"GST pull-down, co-IP, and reporter assays mapping Ptx1 and Egr-1 interactions on LHβ/MIS promoters\",\n      \"pmids\": [\"10369682\", \"10082522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous ligand status of SF-1 unresolved\", \"Promoter-selective contributions not fully dissected\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified PNRC as a ligand-independent coactivator of SF-1, defining a proline-rich SH3-binding contact mechanism for transcriptional enhancement.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, co-IP, reporter assays, and domain mutagenesis\",\n      \"pmids\": [\"10894149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological gene targets of SF-1/PNRC not defined\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Placed NR5A1 within the gonadal developmental hierarchy by identifying WT1(-KTS) and LHX9 as direct upstream transcriptional activators of the Sf1 promoter.\",\n      \"evidence\": \"Promoter binding/transactivation assays and genetic epistasis with gonad-specific knockouts\",\n      \"pmids\": [\"12130543\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial control with repressors not yet integrated\", \"Stage-specific switching not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed that SUMOylation at Lys119 selectively silences SF-1 DNA binding at noncanonical target genes, defining a post-translational mechanism for target-gene discrimination.\",\n      \"evidence\": \"In vitro sumoylation, K119R/K194R mutants, NMR of the LBD, ChIP, and reporter assays\",\n      \"pmids\": [\"18838537\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymes setting/removing SUMO in specific tissues undefined\", \"Genome-wide SUMO-sensitive target catalog incomplete\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed SF1 (the splicing/transcription factor) acts as a tumor-suppressive component of the β-catenin/TCF-4 complex, with the gene being embryonically essential.\",\n      \"evidence\": \"Co-IP, reporter and colony-formation assays, gene-trap knockout mice, and a carcinogen-induced tumor model\",\n      \"pmids\": [\"17900258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of β-catenin/TCF-4 repression unresolved\", \"Whether splicing function contributes to tumor suppression unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined cooperative SF-1/SRY action at the Sox9 Tesco enhancer as the molecular trigger of male sex determination, including a SOX9 feedforward loop.\",\n      \"evidence\": \"ChIP, enhancer mutation, reporter assays, and in vivo sex-reversal genetics\",\n      \"pmids\": [\"18454134\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative thresholds for SF-1 occupancy not defined\", \"Other enhancers co-regulated by this complex not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed Wnt/β-catenin signaling antagonizes SF-1 function by selectively excluding it from the Tesco enhancer without changing its protein levels, establishing locus-selective regulation of SF-1 occupancy.\",\n      \"evidence\": \"ChIP at Tesco and Cyp11a1, Wnt pathway manipulation in embryonic gonad culture\",\n      \"pmids\": [\"22128028\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of selective enhancer exclusion unknown\", \"Generality across SF-1 targets untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the dosage-sensitive sex-reversal mechanism by showing excess DAX1 reduces SF-1 binding to the Tesco enhancer.\",\n      \"evidence\": \"Reporter assays, ChIP for SF-1, Dax1-overexpressing transgenic mice, and Sox9 epistasis\",\n      \"pmids\": [\"22294746\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct structural basis of DAX1-mediated SF-1 displacement unclear\", \"Locus selectivity of DAX1 antagonism not fully mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified FOXL2 as a direct repressor of Sf1 that antagonizes WT1-KTS activation, defining the ovarian arm of Sf1 transcriptional control.\",\n      \"evidence\": \"qRT-PCR, reporter assays, in vitro ChIP, binding-site mutagenesis, and Foxl2-null mice\",\n      \"pmids\": [\"24451388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dynamic balance between FOXL2 and WT1 in vivo not quantified\", \"Downstream consequences of Sf1 derepression incomplete\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated promoter-selective SF-1 functions in humans by showing the R103Q mutation impairs TLX1 transactivation (and spleen development) while sparing SOX9 co-activation.\",\n      \"evidence\": \"Patient mutation analysis and wild-type/mutant SF-1 reporter assays on distinct target promoters\",\n      \"pmids\": [\"24905461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of target-selective loss not resolved\", \"Full spectrum of R103Q-affected targets unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established WT1 as also a repressive controller of Sf1 timing, showing premature Sf1 upregulation upon Wt1 loss redirects somatic cells toward a steroidogenic rather than supporting fate.\",\n      \"evidence\": \"Temporal conditional Wt1 knockout, promoter binding with binding-site mutagenesis, and lineage analysis\",\n      \"pmids\": [\"27888191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Switch between WT1 activator and repressor roles not mechanistically defined\", \"Cofactors mediating WT1 repression unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Refined SF-1 SUMO biology by showing SUMOylation enhances DAX1 recruitment to repress the fetal adrenal enhancer, controlling postnatal adrenal X-zone regression.\",\n      \"evidence\": \"SUMOylation-deficient knock-in mice, Dax1 knockout mice, FAdE-lacZ reporter mice, and interaction assays\",\n      \"pmids\": [\"28893949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMO promotes DAX1 binding mechanistically unclear\", \"Other SUMO-dependent corepressors not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the Mdm2-p53 axis as a transcriptional controller of SF-1 in granulosa cells required for ovulation and fertility.\",\n      \"evidence\": \"Conditional Mdm2 knockouts, Mdm2/p53 double knockout rescue, and fertility/SF-1 expression analysis\",\n      \"pmids\": [\"30260703\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether p53 acts directly on the Sf1 promoter not established\", \"Direct steroidogenic targets affected not fully mapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linked metabolic insulin signaling to adrenal SF-1 levels via FoxO1 suppression, connecting SF-1 to systemic energy state.\",\n      \"evidence\": \"Insulin treatment, FoxO1 overexpression, and insulin-deficient/hyperactive mouse models\",\n      \"pmids\": [\"29567944\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic linkage of insulin signaling to the Sf1 promoter (correlative expression data)\", \"FoxO1 binding to Sf1 regulatory regions not demonstrated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Implicated chromatin-level control of SF-1, showing prenatal nicotine reduces SF-1 promoter histone acetylation via HDAC2 to impair steroidogenesis.\",\n      \"evidence\": \"ChIP for histone marks, bisulfite sequencing, qRT-PCR, and HDAC-inhibitor rescue\",\n      \"pmids\": [\"24709674\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"HDAC2-to-SF-1 link is correlative, not causally established\", \"Direct recruitment of HDAC2 to the Sf1 promoter not shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved within this corpus whether the branchpoint-binding splicing factor SF1 (ZFM1) and the steroidogenic nuclear receptor SF-1 (NR5A1) represent one protein with dual roles or two distinct gene products conflated by symbol, and how their respective regulatory networks intersect.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No timeline discovery reconciles the KH/U2AF65 splicing identity with the DNA-binding NR5A1 nuclear-receptor identity\", \"Cross-talk between splicing and transcriptional/steroidogenic functions not directly tested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 2, 3, 12]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 6, 14, 24]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [15, 24, 28]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 9, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [18, 20, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 15, 24]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [10, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 6, 7, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [21, 24, 23]}\n    ],\n    \"complexes\": [\n      \"pre-spliceosome (E complex)\",\n      \"U2 snRNP-associated branchpoint complex\",\n      \"beta-catenin/TCF-4 transcriptional complex\"\n    ],\n    \"partners\": [\n      \"U2AF65\",\n      \"SF3b1\",\n      \"SF3b4\",\n      \"PRPF40B\",\n      \"CA150\",\n      \"EWS\",\n      \"DAX1\",\n      \"SRY\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}