{"gene":"FIGLA","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1997,"finding":"FIGLA (FIGalpha) is a novel basic helix-loop-helix transcription factor that heterodimerizes with the ubiquitous bHLH protein E12 and binds E-box elements (~200 bp upstream of transcription start sites) in the promoters of all three zona pellucida genes (Zp1, Zp2, Zp3); FIGLA transactivates reporter genes coupled to each of the three mouse zona promoters in heterologous 10T1/2 embryonic fibroblasts.","method":"Electrophoretic mobility shift assay (EMSA), co-immunoprecipitation/protein-DNA complex identification, luciferase reporter transactivation in heterologous fibroblasts","journal":"Development","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical binding assay plus functional transactivation assay; replicated across all three Zp promoters in the same study","pmids":["9362457"],"is_preprint":false},{"year":2000,"finding":"Targeted knockout of FIGalpha in mice causes failure of primordial follicle formation at birth, massive postnatal oocyte depletion, shrunken ovaries, and female sterility; null females fail to express Zp1, Zp2, or Zp3, establishing FIGLA as a key regulator of multiple oocyte-specific genes including zona pellucida genes and genes initiating folliculogenesis. Male FIGalpha null mice are fertile with no obvious phenotype.","method":"Targeted gene knockout in mouse embryonic stem cells, histology, RT-PCR for downstream gene expression","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function mouse model with defined cellular and molecular phenotypes; replicated across multiple litters and analyzed at multiple time points","pmids":["11023867"],"is_preprint":false},{"year":2004,"finding":"Human FIGLA protein heterodimerizes with E12 and binds the E-box of the human ZP2 promoter, as demonstrated by EMSA with in vitro-expressed human FIGLA; similar mobility shifts were detected in human fetal ovary extracts, confirming the interaction occurs in vivo.","method":"EMSA with in vitro-expressed human FIGLA protein and human fetal ovary nuclear extracts","journal":"Molecular human reproduction","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct biochemical reconstitution (EMSA with recombinant protein) corroborated by native fetal ovary extracts in same study","pmids":["15044608"],"is_preprint":false},{"year":2008,"finding":"A FIGLA missense mutation p.140delN (deletion of asparagine 140 in the HLH domain) found in a woman with premature ovarian failure disrupts FIGLA binding to the TCF3 (E12) helix-loop-helix domain, as demonstrated by yeast two-hybrid assay.","method":"Yeast two-hybrid assay comparing wild-type and mutant FIGLA interaction with TCF3 HLH domain","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — yeast two-hybrid is a single method in a single lab; functional disruption of a known FIGLA-E12 interaction is mechanistically informative","pmids":["18499083"],"is_preprint":false},{"year":2013,"finding":"MicroRNA-212 (miR-212) post-transcriptionally represses FIGLA expression by binding a microRNA recognition element (MRE) in the 3' UTR of bovine FIGLA mRNA; ectopic miR-212 expression in bovine early embryos reduces FIGLA protein levels, identifying miR-212 as a negative regulator of FIGLA during the maternal-to-zygotic transition.","method":"Luciferase reporter assay with FIGLA 3' UTR, miR-212 mimic overexpression in bovine embryos with FIGLA protein quantification","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus functional mimic experiment in embryos, two orthogonal methods, single lab","pmids":["24086699"],"is_preprint":false},{"year":2016,"finding":"Bovine LHX8, a germ-cell-specific LIM-homeobox transcription factor, physically interacts with FIGLA; a nuclear localization signal in LHX8 is required for its nuclear import, and LHX8 is predominantly nuclear when ectopically expressed.","method":"Co-immunoprecipitation/yeast two-hybrid-like protein interaction assay (interaction detected); subcellular localization by fluorescence microscopy with deletion constructs","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — novel protein-protein interaction reported in single lab with limited methodological detail in abstract","pmids":["27716808"],"is_preprint":false},{"year":2018,"finding":"In zebrafish, CRISPR/Cas9-mediated disruption of figla blocks the transition of cystic CN-stage oocytes to individual follicular perinucleolar oocytes (stage IB), resulting in an all-male phenotype; this phenotype cannot be rescued by estrogen treatment (unlike cyp19a1a mutants) or by tp53 mutation (unlike fancd1/fancl mutants), placing figla in a distinct epistatic pathway from steroid hormone signaling and p53-dependent apoptosis.","method":"CRISPR/Cas9 knockout in zebrafish, epistasis analysis with cyp19a1a mutants (estrogen rescue), tp53 double mutants, histological and transcriptomic analysis","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR loss-of-function with defined cellular phenotype plus epistasis experiments ruling out alternative pathways; multiple orthogonal approaches","pmids":["30184072"],"is_preprint":false},{"year":2018,"finding":"A homozygous FIGLA mutation c.2T>C (p.Met1Thr) found in two sisters with POI blocks synthesis of full-length FIGLA protein (start codon shift) without affecting FIGLA gene transcription, producing a FIGLA knockout-like phenotype.","method":"In vitro functional analysis of mutant construct (protein synthesis assay), whole-genome sequencing, Sanger sequencing","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro translation/protein expression assay demonstrating loss of full-length protein, single lab","pmids":["30474133"],"is_preprint":false},{"year":2020,"finding":"FIGLA, LHX8, and SOHLH1 physically interact with each other in perinatal oocytes and cross-regulate each other's expression; Figla deficiency disrupts abundance of NOBOX, LHX8, SOHLH1, SOHLH2, and KIT, impedes meiotic progression, causes DNA damage, and results in oocyte apoptosis. Dysregulated genes include meiosis-related genes (Sycp3, Rad51, Ybx2) and oocyte growth genes (Nobox, Lhx8, Taf4b, Sohlh1, Sohlh2, Gdf9).","method":"RNA-seq of perinatal ovaries from FiglaNull, Lhx8Null, and Sohlh1Null mice; co-immunoprecipitation/direct protein interaction assays; immunofluorescence for protein abundance; DNA damage assays (presumably γH2AX or TUNEL); gene expression profiling","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple gene-edited mouse models, global transcriptomics, direct protein interaction assays, and functional cellular readouts (apoptosis, DNA damage) in a single rigorous study","pmids":["32086523"],"is_preprint":false},{"year":2021,"finding":"siRNA-mediated knockdown of Figla in secondary follicle oocytes of mature (but not prepubertal) mice reduces follicle diameter growth in vitro, suggesting Figla promotes secondary follicle growth specifically in adult mice; pathway analysis indicates Figla upregulates VDR/RXR activation and downregulates estrogen signaling and stem cell pluripotency pathways.","method":"Figla siRNA microinjection into secondary follicle oocytes followed by in vitro follicle growth assay; transcriptomic pathway analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct loss-of-function in oocytes with quantitative follicle growth phenotype, single lab, limited mechanistic follow-up","pmids":["33972571"],"is_preprint":false},{"year":2021,"finding":"FIGLA mutations (p.A4E, p.V209I, p.D28E) found in POF patients significantly reduce FIGLA binding to ZP1, ZP2, and ZP3 promoters and reduce transcriptional activation of ZP1, ZP2, and ZP3 reporter genes.","method":"Chromatin immunoprecipitation (ChIP) comparing wild-type vs. mutant FIGLA binding to ZP promoters; luciferase reporter assay in HEK293 cells","journal":"Frontiers in medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (ChIP and reporter assay) in single lab demonstrating reduced promoter binding and reduced transcriptional activation","pmids":["34778283"],"is_preprint":false},{"year":2023,"finding":"In zebrafish, epistasis analysis using figla-/-;dmrt1-/- double mutants shows germ cells remain in cysts without forming follicles in the absence of figla, whereas nobox-/-;dmrt1-/- fish form follicles that arrest at the previtellogenic stage; this places figla specifically upstream of follicle formation (cyst-to-follicle transition) and nobox upstream of subsequent follicle growth and estrogen/aromatase signaling.","method":"CRISPR/Cas9-generated double mutants (figla-/-;dmrt1-/- and nobox-/-;dmrt1-/-), histology, expression analysis of cyp19a1a and other pathway genes, serum estradiol measurement, E2 rescue experiment","journal":"Communications biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous double-mutant epistasis in zebrafish with multiple orthogonal readouts (histology, gene expression, hormone levels, hormone rescue), clearly distinguishing figla and nobox roles","pmids":["37990081"],"is_preprint":false},{"year":2014,"finding":"Live imaging of Figla-Cre;mEGFP/mTomato reporter mice (germ cells green, somatic tissue red) in newborn ovaries shows that few oocytes egress from the ovary and the vast majority are lost within the ovary; macrophage depletion (Csf1op/op mice) does not prevent oocyte loss, but TUNEL assays and caspase inhibitor experiments indicate apoptosis contributes to perinatal oocyte loss.","method":"Live confocal imaging of cultured newborn ovaries, macrophage depletion genetic model (Csf1op/op), TUNEL assay, caspase inhibitor treatment","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live imaging plus genetic and pharmacological experiments; apoptosis conclusion supported by two orthogonal approaches, single lab","pmids":["24400092"],"is_preprint":false}],"current_model":"FIGLA is an oocyte-specific basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with ubiquitous bHLH partners (E12/TCF3) to bind E-box elements in the promoters of zona pellucida genes (ZP1, ZP2, ZP3) and transactivate their expression; it also physically interacts with and cross-regulates other germ-cell transcription factors (LHX8, SOHLH1, NOBOX) in a cooperative network that controls meiotic progression and survival of perinatal oocytes, and is essential for the transition from cystic oocytes to individual primordial follicles, with its maternal mRNA being negatively regulated post-transcriptionally by miR-212 during early embryogenesis."},"narrative":{"mechanistic_narrative":"FIGLA is an oocyte-specific basic helix-loop-helix (bHLH) transcription factor that governs the perinatal transition from cystic oocytes to individual primordial follicles and orchestrates the oocyte-specific gene expression program [PMID:11023867, PMID:30184072]. It functions by heterodimerizing with the ubiquitous bHLH partner E12/TCF3 and binding E-box elements in the promoters of the zona pellucida genes ZP1, ZP2, and ZP3, transactivating their expression; this activity is conserved between mouse and human [PMID:9362457, PMID:15044608]. Beyond zona pellucida regulation, FIGLA operates within a cooperative germ-cell transcription factor network, physically interacting with LHX8 and SOHLH1 and cross-regulating the abundance of NOBOX, SOHLH1/2, and KIT, with its loss impeding meiotic progression, causing DNA damage, and triggering perinatal oocyte apoptosis [PMID:27716808, PMID:32086523, PMID:24400092]. Genetic ablation in mouse and zebrafish establishes FIGLA as essential and non-redundant for follicle formation, acting in a pathway distinct from steroid hormone and p53-dependent apoptotic signaling and upstream of NOBOX-dependent follicle growth [PMID:11023867, PMID:30184072, PMID:37990081]. Multiple loss-of-function and missense mutations that disrupt TCF3 binding or ZP promoter transactivation cause premature ovarian insufficiency in women [PMID:18499083, PMID:30474133, PMID:34778283]. Post-transcriptionally, maternal FIGLA mRNA is repressed by miR-212 binding its 3' UTR during the maternal-to-zygotic transition [PMID:24086699].","teleology":[{"year":1997,"claim":"Established the founding molecular activity of FIGLA: how an oocyte factor could coordinately switch on the zona pellucida genes, by showing it is a bHLH protein that dimerizes with E12 and binds E-boxes in all three Zp promoters.","evidence":"EMSA and luciferase reporter transactivation in heterologous fibroblasts for mouse Zp1/Zp2/Zp3 promoters","pmids":["9362457"],"confidence":"High","gaps":["Done in heterologous fibroblasts, not native oocytes","Full set of in vivo target genes beyond Zp genes unknown","No structural basis for E-box selectivity"]},{"year":2000,"claim":"Demonstrated that FIGLA is physiologically required for primordial follicle formation and female fertility, moving it from a candidate Zp regulator to a master regulator of folliculogenesis.","evidence":"Targeted knockout in mice with histology and RT-PCR of downstream genes","pmids":["11023867"],"confidence":"High","gaps":["Direct vs. indirect cause of oocyte depletion not separated","Mechanism linking FIGLA loss to follicle formation failure unresolved","Male dispensability unexplained"]},{"year":2004,"claim":"Extended the FIGLA-E12/ZP2 mechanism to humans and confirmed it occurs in native tissue, validating the mouse model for human ovarian biology.","evidence":"EMSA with recombinant human FIGLA and human fetal ovary nuclear extracts","pmids":["15044608"],"confidence":"High","gaps":["Only ZP2 promoter tested in human","No functional transactivation shown for human promoters here"]},{"year":2008,"claim":"Linked FIGLA to human disease and pinpointed the mechanism: an HLH-domain deletion in a POI patient abolishes the TCF3/E12 interaction required for DNA binding.","evidence":"Yeast two-hybrid comparing wild-type and p.140delN FIGLA against TCF3 HLH domain","pmids":["18499083"],"confidence":"Medium","gaps":["Single method (Y2H) without biochemical reconstitution","Causality in patient not proven beyond interaction loss","Effect on downstream transactivation not measured"]},{"year":2013,"claim":"Identified post-transcriptional control of FIGLA, showing maternal FIGLA mRNA is actively repressed by miR-212 during the maternal-to-zygotic transition.","evidence":"Luciferase reporter with FIGLA 3' UTR and miR-212 mimic overexpression in bovine embryos","pmids":["24086699"],"confidence":"Medium","gaps":["Shown in bovine; conservation in human/mouse not tested","Physiological consequence of repression on embryo not defined","Single lab"]},{"year":2014,"claim":"Resolved the fate of oocytes lost perinatally, showing intra-ovarian apoptosis rather than egress or macrophage-driven clearance drives the loss.","evidence":"Live imaging of Figla-Cre reporter newborn ovaries, Csf1op/op macrophage depletion, TUNEL and caspase inhibitor experiments","pmids":["24400092"],"confidence":"Medium","gaps":["Causal link between FIGLA activity and apoptosis not directly tested here","Reporter marks germ cells but does not assay FIGLA function","Single lab"]},{"year":2016,"claim":"Began assembling the germ-cell transcription factor network by showing FIGLA physically interacts with the LIM-homeobox factor LHX8.","evidence":"Protein interaction assay and subcellular localization with deletion constructs in bovine system","pmids":["27716808"],"confidence":"Medium","gaps":["Interaction detected with limited methodological detail","Functional consequence of FIGLA-LHX8 binding not defined here","Interaction interface unmapped"]},{"year":2018,"claim":"Placed FIGLA in a defined epistatic pathway for the cyst-to-follicle transition, distinct from estrogen signaling and p53-dependent apoptosis, using zebrafish loss-of-function and rescue logic.","evidence":"CRISPR/Cas9 figla knockout in zebrafish with estrogen rescue and tp53 double-mutant epistasis, histology and transcriptomics","pmids":["30184072"],"confidence":"High","gaps":["Molecular targets driving the cyst-to-follicle block not identified","All-male phenotype mechanism in fish vs. mammals differs","Direct vs. indirect transcriptional effects unseparated"]},{"year":2018,"claim":"Strengthened FIGLA as a POI gene by identifying a start-codon mutation that ablates full-length protein synthesis without affecting transcription, recapitulating a knockout-like state.","evidence":"In vitro protein synthesis assay of c.2T>C construct, whole-genome and Sanger sequencing of two affected sisters","pmids":["30474133"],"confidence":"Medium","gaps":["In vitro translation only; no patient-derived protein measured","Functional ovarian consequence inferred from knockout analogy","Single family"]},{"year":2020,"claim":"Defined the cooperative core of the network, showing FIGLA, LHX8 and SOHLH1 mutually interact and cross-regulate, and that FIGLA loss disrupts meiotic progression, causes DNA damage, and triggers apoptosis.","evidence":"RNA-seq across FiglaNull/Lhx8Null/Sohlh1Null mice, co-IP protein interaction assays, immunofluorescence, and DNA damage/apoptosis readouts","pmids":["32086523"],"confidence":"High","gaps":["Direct FIGLA target promoters vs. secondary network effects not fully separated","Order of network activation not resolved","Mechanism connecting FIGLA loss to DNA damage unclear"]},{"year":2021,"claim":"Refined FIGLA's transactivation defect as the disease mechanism, showing POF-associated missense variants reduce ZP promoter binding and transcriptional activation.","evidence":"ChIP of wild-type vs. mutant FIGLA on ZP promoters and luciferase reporter assays in HEK293 cells","pmids":["34778283"],"confidence":"Medium","gaps":["Performed in heterologous HEK293 cells","In vivo consequence in patient oocytes not shown","Single lab"]},{"year":2021,"claim":"Extended FIGLA function beyond primordial follicle formation, showing a stage- and age-specific role in promoting secondary follicle growth in adult oocytes.","evidence":"Figla siRNA microinjection into secondary follicle oocytes with in vitro growth assay and transcriptomic pathway analysis","pmids":["33972571"],"confidence":"Medium","gaps":["Pathway changes (VDR/RXR, estrogen) inferred from transcriptomics, not validated","Limited mechanistic follow-up","Single lab"]},{"year":2023,"claim":"Ordered the network in vivo by epistasis, placing figla specifically at the cyst-to-follicle transition upstream of nobox-dependent follicle growth and aromatase/estrogen signaling.","evidence":"CRISPR figla-/-;dmrt1-/- and nobox-/-;dmrt1-/- zebrafish double mutants with histology, gene expression, estradiol measurement and E2 rescue","pmids":["37990081"],"confidence":"High","gaps":["Direct transcriptional targets mediating the cyst-to-follicle step unidentified","Mammalian conservation of figla-nobox ordering not directly tested","How figla loss arrests cells in cysts molecularly unresolved"]},{"year":null,"claim":"The complete genome-wide set of direct FIGLA targets and the structural/biochemical basis by which the FIGLA-E12 dimer selects oocyte-specific E-boxes remain undefined.","evidence":"No discovery in the timeline provides genome-wide direct binding maps or structural data for the FIGLA-E12 complex","pmids":[],"confidence":"Low","gaps":["No ChIP-seq/CUT&RUN target catalog","No structure of FIGLA-E12-DNA complex","Mechanism linking transcriptional output to meiotic progression and DNA-damage avoidance unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,2,10]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,2,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,6,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[1,6,8]}],"complexes":[],"partners":["TCF3","LHX8","SOHLH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6QHK4","full_name":"Factor in the germline alpha","aliases":["Class C basic helix-loop-helix protein 8","bHLHc8","Folliculogenesis-specific basic helix-loop-helix protein","Transcription factor FIGa"],"length_aa":219,"mass_kda":24.1,"function":"Germline specific transcription factor implicated in postnatal oocyte-specific gene expression. Plays a key regulatory role in the expression of multiple oocyte-specific genes, including those that initiate folliculogenesis and those that encode the zona pellucida (ZP1, ZP2 and ZP3) required for fertilization and early embryonic survival. Essential for oocytes to survive and form primordial follicles. The persistence of FIGLA in adult females suggests that it may regulate additional pathways that are essential for normal ovarian development. Binds to the E-box (5'-CANNTG-3') of the ZPs (ZP1, ZP2, ZP3) promoters","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6QHK4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FIGLA","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FIGLA","total_profiled":1310},"omim":[{"mim_id":"618014","title":"PREMATURE OVARIAN FAILURE 14; POF14","url":"https://www.omim.org/entry/618014"},{"mim_id":"612310","title":"PREMATURE OVARIAN FAILURE 6; POF6","url":"https://www.omim.org/entry/612310"},{"mim_id":"610224","title":"SPERMATOGENESIS- AND OOGENESIS-SPECIFIC BASIC HELIX-LOOP-HELIX PROTEIN 1; SOHLH1","url":"https://www.omim.org/entry/610224"},{"mim_id":"608697","title":"FOLLICULOGENESIS-SPECIFIC bHLH TRANSCRIPTION FACTOR; FIGLA","url":"https://www.omim.org/entry/608697"},{"mim_id":"311360","title":"PREMATURE OVARIAN FAILURE 1; POF1","url":"https://www.omim.org/entry/311360"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"ovary","ntpm":2.9},{"tissue":"retina","ntpm":1.0}],"url":"https://www.proteinatlas.org/search/FIGLA"},"hgnc":{"alias_symbol":["bHLHc8","Figalpha"],"prev_symbol":[]},"alphafold":{"accession":"Q6QHK4","domains":[{"cath_id":"4.10.280.10","chopping":"46-127","consensus_level":"medium","plddt":93.5532,"start":46,"end":127}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6QHK4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6QHK4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6QHK4-F1-predicted_aligned_error_v6.png","plddt_mean":71.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FIGLA","jax_strain_url":"https://www.jax.org/strain/search?query=FIGLA"},"sequence":{"accession":"Q6QHK4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6QHK4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6QHK4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6QHK4"}},"corpus_meta":[{"pmid":"11023867","id":"PMC_11023867","title":"FIGalpha, 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oocytes of ovotestes through the Figla-independent pathway in the hermaphroditic black porgy, Acanthopagrus schlegelii.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29073214","citation_count":8,"is_preprint":false},{"pmid":"34778283","id":"PMC_34778283","title":"Mutations in FIGLA Associated With Premature Ovarian Insufficiency in a Chinese Population.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34778283","citation_count":4,"is_preprint":false},{"pmid":"38338134","id":"PMC_38338134","title":"Molecular Characterization, Expression Pattern, DNA Methylation and Gene Disruption of Figla in Blotched Snakehead (Channa maculata).","date":"2024","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/38338134","citation_count":3,"is_preprint":false},{"pmid":"32507252","id":"PMC_32507252","title":"Transcriptional activity of FIGLA, NEUROG2, and EGR1 transcription factors associated with polymorphisms in the proximal regulatory region of GPR54 gene in cattle.","date":"2020","source":"Animal reproduction science","url":"https://pubmed.ncbi.nlm.nih.gov/32507252","citation_count":3,"is_preprint":false},{"pmid":"25652828","id":"PMC_25652828","title":"A lentiviral vector visualizing the germ cell specification in vitro under the control of Figla promoter.","date":"2015","source":"Applied biochemistry and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/25652828","citation_count":3,"is_preprint":false},{"pmid":"39896098","id":"PMC_39896098","title":"Homozygous FIGLA missense variant in two Japanese sisters with primary ovarian insufficiency: Case reports and literature review.","date":"2025","source":"Reproductive medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/39896098","citation_count":1,"is_preprint":false},{"pmid":"42140582","id":"PMC_42140582","title":"A duplicated female pathway gene figla-like evolves as the male sex-determining gene in 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reporter genes coupled to each of the three mouse zona promoters in heterologous 10T1/2 embryonic fibroblasts.\",\n      \"method\": \"Electrophoretic mobility shift assay (EMSA), co-immunoprecipitation/protein-DNA complex identification, luciferase reporter transactivation in heterologous fibroblasts\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical binding assay plus functional transactivation assay; replicated across all three Zp promoters in the same study\",\n      \"pmids\": [\"9362457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Targeted knockout of FIGalpha in mice causes failure of primordial follicle formation at birth, massive postnatal oocyte depletion, shrunken ovaries, and female sterility; null females fail to express Zp1, Zp2, or Zp3, establishing FIGLA as a key regulator of multiple oocyte-specific genes including zona pellucida genes and genes initiating folliculogenesis. Male FIGalpha null mice are fertile with no obvious phenotype.\",\n      \"method\": \"Targeted gene knockout in mouse embryonic stem cells, histology, RT-PCR for downstream gene expression\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function mouse model with defined cellular and molecular phenotypes; replicated across multiple litters and analyzed at multiple time points\",\n      \"pmids\": [\"11023867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human FIGLA protein heterodimerizes with E12 and binds the E-box of the human ZP2 promoter, as demonstrated by EMSA with in vitro-expressed human FIGLA; similar mobility shifts were detected in human fetal ovary extracts, confirming the interaction occurs in vivo.\",\n      \"method\": \"EMSA with in vitro-expressed human FIGLA protein and human fetal ovary nuclear extracts\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical reconstitution (EMSA with recombinant protein) corroborated by native fetal ovary extracts in same study\",\n      \"pmids\": [\"15044608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A FIGLA missense mutation p.140delN (deletion of asparagine 140 in the HLH domain) found in a woman with premature ovarian failure disrupts FIGLA binding to the TCF3 (E12) helix-loop-helix domain, as demonstrated by yeast two-hybrid assay.\",\n      \"method\": \"Yeast two-hybrid assay comparing wild-type and mutant FIGLA interaction with TCF3 HLH domain\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — yeast two-hybrid is a single method in a single lab; functional disruption of a known FIGLA-E12 interaction is mechanistically informative\",\n      \"pmids\": [\"18499083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MicroRNA-212 (miR-212) post-transcriptionally represses FIGLA expression by binding a microRNA recognition element (MRE) in the 3' UTR of bovine FIGLA mRNA; ectopic miR-212 expression in bovine early embryos reduces FIGLA protein levels, identifying miR-212 as a negative regulator of FIGLA during the maternal-to-zygotic transition.\",\n      \"method\": \"Luciferase reporter assay with FIGLA 3' UTR, miR-212 mimic overexpression in bovine embryos with FIGLA protein quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus functional mimic experiment in embryos, two orthogonal methods, single lab\",\n      \"pmids\": [\"24086699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Bovine LHX8, a germ-cell-specific LIM-homeobox transcription factor, physically interacts with FIGLA; a nuclear localization signal in LHX8 is required for its nuclear import, and LHX8 is predominantly nuclear when ectopically expressed.\",\n      \"method\": \"Co-immunoprecipitation/yeast two-hybrid-like protein interaction assay (interaction detected); subcellular localization by fluorescence microscopy with deletion constructs\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — novel protein-protein interaction reported in single lab with limited methodological detail in abstract\",\n      \"pmids\": [\"27716808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In zebrafish, CRISPR/Cas9-mediated disruption of figla blocks the transition of cystic CN-stage oocytes to individual follicular perinucleolar oocytes (stage IB), resulting in an all-male phenotype; this phenotype cannot be rescued by estrogen treatment (unlike cyp19a1a mutants) or by tp53 mutation (unlike fancd1/fancl mutants), placing figla in a distinct epistatic pathway from steroid hormone signaling and p53-dependent apoptosis.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, epistasis analysis with cyp19a1a mutants (estrogen rescue), tp53 double mutants, histological and transcriptomic analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR loss-of-function with defined cellular phenotype plus epistasis experiments ruling out alternative pathways; multiple orthogonal approaches\",\n      \"pmids\": [\"30184072\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A homozygous FIGLA mutation c.2T>C (p.Met1Thr) found in two sisters with POI blocks synthesis of full-length FIGLA protein (start codon shift) without affecting FIGLA gene transcription, producing a FIGLA knockout-like phenotype.\",\n      \"method\": \"In vitro functional analysis of mutant construct (protein synthesis assay), whole-genome sequencing, Sanger sequencing\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro translation/protein expression assay demonstrating loss of full-length protein, single lab\",\n      \"pmids\": [\"30474133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FIGLA, LHX8, and SOHLH1 physically interact with each other in perinatal oocytes and cross-regulate each other's expression; Figla deficiency disrupts abundance of NOBOX, LHX8, SOHLH1, SOHLH2, and KIT, impedes meiotic progression, causes DNA damage, and results in oocyte apoptosis. Dysregulated genes include meiosis-related genes (Sycp3, Rad51, Ybx2) and oocyte growth genes (Nobox, Lhx8, Taf4b, Sohlh1, Sohlh2, Gdf9).\",\n      \"method\": \"RNA-seq of perinatal ovaries from FiglaNull, Lhx8Null, and Sohlh1Null mice; co-immunoprecipitation/direct protein interaction assays; immunofluorescence for protein abundance; DNA damage assays (presumably γH2AX or TUNEL); gene expression profiling\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple gene-edited mouse models, global transcriptomics, direct protein interaction assays, and functional cellular readouts (apoptosis, DNA damage) in a single rigorous study\",\n      \"pmids\": [\"32086523\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"siRNA-mediated knockdown of Figla in secondary follicle oocytes of mature (but not prepubertal) mice reduces follicle diameter growth in vitro, suggesting Figla promotes secondary follicle growth specifically in adult mice; pathway analysis indicates Figla upregulates VDR/RXR activation and downregulates estrogen signaling and stem cell pluripotency pathways.\",\n      \"method\": \"Figla siRNA microinjection into secondary follicle oocytes followed by in vitro follicle growth assay; transcriptomic pathway analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct loss-of-function in oocytes with quantitative follicle growth phenotype, single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"33972571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FIGLA mutations (p.A4E, p.V209I, p.D28E) found in POF patients significantly reduce FIGLA binding to ZP1, ZP2, and ZP3 promoters and reduce transcriptional activation of ZP1, ZP2, and ZP3 reporter genes.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) comparing wild-type vs. mutant FIGLA binding to ZP promoters; luciferase reporter assay in HEK293 cells\",\n      \"journal\": \"Frontiers in medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (ChIP and reporter assay) in single lab demonstrating reduced promoter binding and reduced transcriptional activation\",\n      \"pmids\": [\"34778283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In zebrafish, epistasis analysis using figla-/-;dmrt1-/- double mutants shows germ cells remain in cysts without forming follicles in the absence of figla, whereas nobox-/-;dmrt1-/- fish form follicles that arrest at the previtellogenic stage; this places figla specifically upstream of follicle formation (cyst-to-follicle transition) and nobox upstream of subsequent follicle growth and estrogen/aromatase signaling.\",\n      \"method\": \"CRISPR/Cas9-generated double mutants (figla-/-;dmrt1-/- and nobox-/-;dmrt1-/-), histology, expression analysis of cyp19a1a and other pathway genes, serum estradiol measurement, E2 rescue experiment\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous double-mutant epistasis in zebrafish with multiple orthogonal readouts (histology, gene expression, hormone levels, hormone rescue), clearly distinguishing figla and nobox roles\",\n      \"pmids\": [\"37990081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Live imaging of Figla-Cre;mEGFP/mTomato reporter mice (germ cells green, somatic tissue red) in newborn ovaries shows that few oocytes egress from the ovary and the vast majority are lost within the ovary; macrophage depletion (Csf1op/op mice) does not prevent oocyte loss, but TUNEL assays and caspase inhibitor experiments indicate apoptosis contributes to perinatal oocyte loss.\",\n      \"method\": \"Live confocal imaging of cultured newborn ovaries, macrophage depletion genetic model (Csf1op/op), TUNEL assay, caspase inhibitor treatment\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live imaging plus genetic and pharmacological experiments; apoptosis conclusion supported by two orthogonal approaches, single lab\",\n      \"pmids\": [\"24400092\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FIGLA is an oocyte-specific basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with ubiquitous bHLH partners (E12/TCF3) to bind E-box elements in the promoters of zona pellucida genes (ZP1, ZP2, ZP3) and transactivate their expression; it also physically interacts with and cross-regulates other germ-cell transcription factors (LHX8, SOHLH1, NOBOX) in a cooperative network that controls meiotic progression and survival of perinatal oocytes, and is essential for the transition from cystic oocytes to individual primordial follicles, with its maternal mRNA being negatively regulated post-transcriptionally by miR-212 during early embryogenesis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FIGLA is an oocyte-specific basic helix-loop-helix (bHLH) transcription factor that governs the perinatal transition from cystic oocytes to individual primordial follicles and orchestrates the oocyte-specific gene expression program [#1, #6]. It functions by heterodimerizing with the ubiquitous bHLH partner E12/TCF3 and binding E-box elements in the promoters of the zona pellucida genes ZP1, ZP2, and ZP3, transactivating their expression; this activity is conserved between mouse and human [#0, #2]. Beyond zona pellucida regulation, FIGLA operates within a cooperative germ-cell transcription factor network, physically interacting with LHX8 and SOHLH1 and cross-regulating the abundance of NOBOX, SOHLH1/2, and KIT, with its loss impeding meiotic progression, causing DNA damage, and triggering perinatal oocyte apoptosis [#5, #8, #12]. Genetic ablation in mouse and zebrafish establishes FIGLA as essential and non-redundant for follicle formation, acting in a pathway distinct from steroid hormone and p53-dependent apoptotic signaling and upstream of NOBOX-dependent follicle growth [#1, #6, #11]. Multiple loss-of-function and missense mutations that disrupt TCF3 binding or ZP promoter transactivation cause premature ovarian insufficiency in women [#3, #7, #10]. Post-transcriptionally, maternal FIGLA mRNA is repressed by miR-212 binding its 3' UTR during the maternal-to-zygotic transition [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established the founding molecular activity of FIGLA: how an oocyte factor could coordinately switch on the zona pellucida genes, by showing it is a bHLH protein that dimerizes with E12 and binds E-boxes in all three Zp promoters.\",\n      \"evidence\": \"EMSA and luciferase reporter transactivation in heterologous fibroblasts for mouse Zp1/Zp2/Zp3 promoters\",\n      \"pmids\": [\"9362457\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done in heterologous fibroblasts, not native oocytes\", \"Full set of in vivo target genes beyond Zp genes unknown\", \"No structural basis for E-box selectivity\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Demonstrated that FIGLA is physiologically required for primordial follicle formation and female fertility, moving it from a candidate Zp regulator to a master regulator of folliculogenesis.\",\n      \"evidence\": \"Targeted knockout in mice with histology and RT-PCR of downstream genes\",\n      \"pmids\": [\"11023867\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect cause of oocyte depletion not separated\", \"Mechanism linking FIGLA loss to follicle formation failure unresolved\", \"Male dispensability unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended the FIGLA-E12/ZP2 mechanism to humans and confirmed it occurs in native tissue, validating the mouse model for human ovarian biology.\",\n      \"evidence\": \"EMSA with recombinant human FIGLA and human fetal ovary nuclear extracts\",\n      \"pmids\": [\"15044608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Only ZP2 promoter tested in human\", \"No functional transactivation shown for human promoters here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked FIGLA to human disease and pinpointed the mechanism: an HLH-domain deletion in a POI patient abolishes the TCF3/E12 interaction required for DNA binding.\",\n      \"evidence\": \"Yeast two-hybrid comparing wild-type and p.140delN FIGLA against TCF3 HLH domain\",\n      \"pmids\": [\"18499083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method (Y2H) without biochemical reconstitution\", \"Causality in patient not proven beyond interaction loss\", \"Effect on downstream transactivation not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified post-transcriptional control of FIGLA, showing maternal FIGLA mRNA is actively repressed by miR-212 during the maternal-to-zygotic transition.\",\n      \"evidence\": \"Luciferase reporter with FIGLA 3' UTR and miR-212 mimic overexpression in bovine embryos\",\n      \"pmids\": [\"24086699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Shown in bovine; conservation in human/mouse not tested\", \"Physiological consequence of repression on embryo not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the fate of oocytes lost perinatally, showing intra-ovarian apoptosis rather than egress or macrophage-driven clearance drives the loss.\",\n      \"evidence\": \"Live imaging of Figla-Cre reporter newborn ovaries, Csf1op/op macrophage depletion, TUNEL and caspase inhibitor experiments\",\n      \"pmids\": [\"24400092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between FIGLA activity and apoptosis not directly tested here\", \"Reporter marks germ cells but does not assay FIGLA function\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Began assembling the germ-cell transcription factor network by showing FIGLA physically interacts with the LIM-homeobox factor LHX8.\",\n      \"evidence\": \"Protein interaction assay and subcellular localization with deletion constructs in bovine system\",\n      \"pmids\": [\"27716808\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interaction detected with limited methodological detail\", \"Functional consequence of FIGLA-LHX8 binding not defined here\", \"Interaction interface unmapped\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed FIGLA in a defined epistatic pathway for the cyst-to-follicle transition, distinct from estrogen signaling and p53-dependent apoptosis, using zebrafish loss-of-function and rescue logic.\",\n      \"evidence\": \"CRISPR/Cas9 figla knockout in zebrafish with estrogen rescue and tp53 double-mutant epistasis, histology and transcriptomics\",\n      \"pmids\": [\"30184072\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular targets driving the cyst-to-follicle block not identified\", \"All-male phenotype mechanism in fish vs. mammals differs\", \"Direct vs. indirect transcriptional effects unseparated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Strengthened FIGLA as a POI gene by identifying a start-codon mutation that ablates full-length protein synthesis without affecting transcription, recapitulating a knockout-like state.\",\n      \"evidence\": \"In vitro protein synthesis assay of c.2T>C construct, whole-genome and Sanger sequencing of two affected sisters\",\n      \"pmids\": [\"30474133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro translation only; no patient-derived protein measured\", \"Functional ovarian consequence inferred from knockout analogy\", \"Single family\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the cooperative core of the network, showing FIGLA, LHX8 and SOHLH1 mutually interact and cross-regulate, and that FIGLA loss disrupts meiotic progression, causes DNA damage, and triggers apoptosis.\",\n      \"evidence\": \"RNA-seq across FiglaNull/Lhx8Null/Sohlh1Null mice, co-IP protein interaction assays, immunofluorescence, and DNA damage/apoptosis readouts\",\n      \"pmids\": [\"32086523\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FIGLA target promoters vs. secondary network effects not fully separated\", \"Order of network activation not resolved\", \"Mechanism connecting FIGLA loss to DNA damage unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined FIGLA's transactivation defect as the disease mechanism, showing POF-associated missense variants reduce ZP promoter binding and transcriptional activation.\",\n      \"evidence\": \"ChIP of wild-type vs. mutant FIGLA on ZP promoters and luciferase reporter assays in HEK293 cells\",\n      \"pmids\": [\"34778283\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in heterologous HEK293 cells\", \"In vivo consequence in patient oocytes not shown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended FIGLA function beyond primordial follicle formation, showing a stage- and age-specific role in promoting secondary follicle growth in adult oocytes.\",\n      \"evidence\": \"Figla siRNA microinjection into secondary follicle oocytes with in vitro growth assay and transcriptomic pathway analysis\",\n      \"pmids\": [\"33972571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway changes (VDR/RXR, estrogen) inferred from transcriptomics, not validated\", \"Limited mechanistic follow-up\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Ordered the network in vivo by epistasis, placing figla specifically at the cyst-to-follicle transition upstream of nobox-dependent follicle growth and aromatase/estrogen signaling.\",\n      \"evidence\": \"CRISPR figla-/-;dmrt1-/- and nobox-/-;dmrt1-/- zebrafish double mutants with histology, gene expression, estradiol measurement and E2 rescue\",\n      \"pmids\": [\"37990081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct transcriptional targets mediating the cyst-to-follicle step unidentified\", \"Mammalian conservation of figla-nobox ordering not directly tested\", \"How figla loss arrests cells in cysts molecularly unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The complete genome-wide set of direct FIGLA targets and the structural/biochemical basis by which the FIGLA-E12 dimer selects oocyte-specific E-boxes remain undefined.\",\n      \"evidence\": \"No discovery in the timeline provides genome-wide direct binding maps or structural data for the FIGLA-E12 complex\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ChIP-seq/CUT&RUN target catalog\", \"No structure of FIGLA-E12-DNA complex\", \"Mechanism linking transcriptional output to meiotic progression and DNA-damage avoidance unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 2, 10]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 2, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 6, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [1, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TCF3\", \"LHX8\", \"SOHLH1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}