{"gene":"FST","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2014,"finding":"ERRβ transcriptionally activates FST in breast cancer cells; chromatin immunoprecipitation identified FST as a direct ERRβ transcriptional target. Overexpressed ERRβ induced FST-mediated apoptosis and enhanced E-cadherin expression through FST upregulation. Additionally, ERRβ-mediated upregulation of BCAS2 inhibited FST transcription by downregulating β-catenin/TCF4 recruitment to the FST promoter.","method":"ChIP cloning, gel supershift assay, co-immunoprecipitation, western blotting, confocal microscopy, qRT-PCR","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and ChIP with multiple orthogonal methods in single lab; functional consequences (apoptosis, E-cadherin) measured but not independently replicated","pmids":["24667650"],"is_preprint":false},{"year":2023,"finding":"FST is expressed in buffalo ovarian follicles at multiple stages and during oocyte maturation; FST overexpression promoted in vitro oocyte maturation rate and blastocyst development. FST knockdown in cumulus cells caused abnormal mitochondrial localization, reduced cumulus expansion, and decreased cleavage/blastocyst rates after parthenogenetic activation. Mechanistically, FST overexpression upregulated Bcl-2, TGF-β, SMAD2, and SMAD3 while downregulating SMAD4 and BAX, indicating FST acts through the TGF-β/SMAD pathway to regulate oocyte maturation and cumulus cell apoptosis.","method":"siRNA knockdown, overexpression vector (pcDNA3.1-EGFP-FST), RT-qPCR, immunostaining, mitochondrial localization assay, parthenogenetic activation assay","journal":"Reproduction in domestic animals","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function with defined phenotypic readouts and pathway gene expression, single lab","pmids":["37917549"],"is_preprint":false},{"year":2016,"finding":"FST mRNA levels decreased from weaning to estrus in porcine ovary, and FSH treatment (250 ng/ml) sharply decreased FST expression in porcine granulosa cells. Knockdown of FST by siRNA significantly increased granulosa cell proliferation and estrogen secretion, establishing FST as a negative regulator of follicle growth and granulosa cell function.","method":"siRNA knockdown, real-time PCR, cell proliferation assay, estrogen secretion measurement","journal":"Animal biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined cellular phenotypes (proliferation, estrogen secretion), single lab, single study","pmids":["27565874"],"is_preprint":false},{"year":2025,"finding":"In goose skeletal muscle satellite cells (SMSCs), overexpression of FST downregulated stemness markers PAX7 and PAX3 and myogenic regulators (MYOG, MYOD, MYF5), while upregulating lipid metabolism genes (PPARG, FABP5, ACSL5) and myosin-related genes. Pathway analysis linked FST-regulated genes to TGF-β, PPAR, fatty acid metabolism, and Notch signaling pathways, indicating a dual regulatory role in skeletal muscle development and lipid metabolism.","method":"Overexpression in SMSCs, comparative transcriptome analysis (RNA-seq), qRT-PCR validation","journal":"Animals","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single overexpression experiment with transcriptome readout, no loss-of-function or protein-level mechanistic validation, single lab","pmids":["41153936"],"is_preprint":false}],"current_model":"Follistatin (FST) is an activin-binding protein that functions as a negative regulator of follicle growth and granulosa cell function (suppressing proliferation and estrogen secretion); it is transcriptionally regulated by ERRβ (directly) and negatively by ERRβ-induced BCAS2 (via β-catenin/TCF4), promotes oocyte maturation and early embryonic development through the TGF-β/SMAD pathway, and modulates skeletal muscle development by suppressing myogenic regulatory factors while upregulating lipid metabolism genes."},"narrative":{"mechanistic_narrative":"Follistatin (FST) acts as a negative regulator of ovarian follicle growth and granulosa cell function, where its knockdown increases granulosa cell proliferation and estrogen secretion and FSH treatment sharply downregulates its expression [PMID:27565874]. In oocytes and cumulus cells, FST promotes in vitro oocyte maturation, cumulus expansion, and early embryonic (blastocyst) development, acting through the TGF-β/SMAD pathway by upregulating TGF-β, SMAD2, SMAD3, and the anti-apoptotic factor Bcl-2 while downregulating SMAD4 and BAX [PMID:37917549]. FST transcription is directly activated by ERRβ, which binds the FST promoter and drives FST-mediated apoptosis and E-cadherin upregulation in breast cancer cells; ERRβ also indirectly represses FST via BCAS2-dependent downregulation of β-catenin/TCF4 recruitment to the FST promoter [PMID:24667650]. Beyond reproductive and transcriptional contexts, FST overexpression suppresses myogenic regulators (PAX7, PAX3, MYOG, MYOD, MYF5) while inducing lipid-metabolism genes, linking it to muscle development and lipid handling [PMID:41153936].","teleology":[{"year":2014,"claim":"Established how FST expression is controlled at the transcriptional level, identifying FST as a direct ERRβ target with both positive and indirect negative regulatory arms.","evidence":"ChIP cloning, gel supershift, Co-IP, and qRT-PCR in breast cancer cells","pmids":["24667650"],"confidence":"Medium","gaps":["Functional consequences (apoptosis, E-cadherin) measured in a single lab without independent replication","Does not address FST's secreted ligand-binding activity"]},{"year":2016,"claim":"Defined FST as a negative regulator of follicle growth, showing it restrains granulosa cell proliferation and estrogen output downstream of FSH.","evidence":"siRNA knockdown with proliferation and estrogen secretion assays in porcine granulosa cells","pmids":["27565874"],"confidence":"Medium","gaps":["Single study, single species","Molecular mechanism linking FST loss to proliferation not resolved"]},{"year":2023,"claim":"Connected FST to oocyte maturation and early embryo development, placing its action within the TGF-β/SMAD pathway and cumulus cell survival.","evidence":"siRNA knockdown and overexpression with maturation, mitochondrial localization, and parthenogenetic activation assays in buffalo follicles","pmids":["37917549"],"confidence":"Medium","gaps":["Pathway inference rests on expression of SMAD genes, not direct SMAD activation readouts","Single lab"]},{"year":2025,"claim":"Extended FST function beyond reproduction, implicating it in suppressing myogenic differentiation while promoting lipid metabolism in muscle satellite cells.","evidence":"Overexpression with RNA-seq and qRT-PCR validation in goose skeletal muscle satellite cells","pmids":["41153936"],"confidence":"Low","gaps":["Single overexpression experiment with no loss-of-function","No protein-level mechanistic validation"]},{"year":null,"claim":"The direct molecular activity of FST as a secreted binding protein (e.g. its ligand targets and binding mechanism) is not characterized in the available corpus.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical binding data in timeline","Cross-tissue mechanism (reproduction vs muscle) not unified by direct experiment"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,2]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P19883","full_name":"Follistatin","aliases":["Activin-binding protein"],"length_aa":344,"mass_kda":38.0,"function":"Multifunctional regulatory protein whose primary function is to antagonize members of the transforming growth factor beta (TGF-beta) superfamily including activin, myostatin, GDF11 or bone morphogenetic proteins (BMPs) (PubMed:11279126, PubMed:16482217, PubMed:18535106). Mechanistically, binds to these ligands in the extracellular space, blocking their type II receptor-binding site to inhibit downstream signaling (PubMed:16482217). Plays an essential role in muscle fiber formation and growth both by preventing the repressive effects of myostatin and through SMAD3/AKT/mTOR signaling independently of myostatin (By similarity). Also promotes neural differentiation by antagonizing the action BMP4 (By similarity). Acts as a specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (FSH) by sequestering activin A/INHBA (PubMed:11279126). On the other hand, translocates into the nucleus where it down-regulates rRNA synthesis and ribosome biogenesis to maintain cellular energy homeostasis by binding to rDNA","subcellular_location":"Secreted; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P19883/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FST","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/FST","total_profiled":1310},"omim":[{"mim_id":"616634","title":"SUSHI, NIDOGEN, AND EGF-LIKE DOMAINS PROTEIN 1; SNED1","url":"https://www.omim.org/entry/616634"},{"mim_id":"612849","title":"UBIQUITIN-SPECIFIC PEPTIDASE 46; USP46","url":"https://www.omim.org/entry/612849"},{"mim_id":"612031","title":"INHIBIN, BETA E; INHBE","url":"https://www.omim.org/entry/612031"},{"mim_id":"611755","title":"LEBER CONGENITAL AMAUROSIS 10; LCA10","url":"https://www.omim.org/entry/611755"},{"mim_id":"610142","title":"CENTROSOMAL PROTEIN, 290-KD; CEP290","url":"https://www.omim.org/entry/610142"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":66.8}],"url":"https://www.proteinatlas.org/search/FST"},"hgnc":{"alias_symbol":["FS"],"prev_symbol":[]},"alphafold":{"accession":"P19883","domains":[{"cath_id":"3.90.290.10","chopping":"28-119","consensus_level":"medium","plddt":93.9335,"start":28,"end":119},{"cath_id":"3.30.60.30","chopping":"130-189","consensus_level":"high","plddt":97.7512,"start":130,"end":189},{"cath_id":"3.30.60.30","chopping":"201-239","consensus_level":"medium","plddt":97.5651,"start":201,"end":239},{"cath_id":"3.30.60.30","chopping":"243-317","consensus_level":"medium","plddt":93.7996,"start":243,"end":317}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P19883","model_url":"https://alphafold.ebi.ac.uk/files/AF-P19883-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P19883-F1-predicted_aligned_error_v6.png","plddt_mean":88.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FST","jax_strain_url":"https://www.jax.org/strain/search?query=FST"},"sequence":{"accession":"P19883","fasta_url":"https://rest.uniprot.org/uniprotkb/P19883.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P19883/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P19883"}},"corpus_meta":[{"pmid":"10098262","id":"PMC_10098262","title":"Indirect measures of gene flow and migration: FST not equal to 1/(4Nm + 1).","date":"1999","source":"Heredity","url":"https://pubmed.ncbi.nlm.nih.gov/10098262","citation_count":700,"is_preprint":false},{"pmid":"21429174","id":"PMC_21429174","title":"Comparison of F(ST) outlier tests for SNP loci under selection.","date":"2011","source":"Molecular ecology resources","url":"https://pubmed.ncbi.nlm.nih.gov/21429174","citation_count":305,"is_preprint":false},{"pmid":"21375616","id":"PMC_21375616","title":"G'ST and D do not replace FST.","date":"2011","source":"Molecular ecology","url":"https://pubmed.ncbi.nlm.nih.gov/21375616","citation_count":175,"is_preprint":false},{"pmid":"17284219","id":"PMC_17284219","title":"Divergent selection as revealed by P(ST) and QTL-based F(ST) in three-spined stickleback (Gasterosteus aculeatus) populations along a coastal-inland gradient.","date":"2007","source":"Molecular ecology","url":"https://pubmed.ncbi.nlm.nih.gov/17284219","citation_count":91,"is_preprint":false},{"pmid":"2016058","id":"PMC_2016058","title":"FST in a hierarchical island model.","date":"1991","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2016058","citation_count":83,"is_preprint":false},{"pmid":"27082756","id":"PMC_27082756","title":"Population-specific FST values for forensic STR markers: A worldwide survey.","date":"2016","source":"Forensic science international. 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Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35430885","citation_count":13,"is_preprint":false},{"pmid":"863462","id":"PMC_863462","title":"The use of the FST statistic of Wright for estimating the effects of genetic drift, selection and migration populations, with special reference to Ireland.","date":"1977","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/863462","citation_count":13,"is_preprint":false},{"pmid":"35464836","id":"PMC_35464836","title":"Genome-Wide Association Study and FST Analysis Reveal Four Quantitative Trait Loci and Six Candidate Genes for Meat Color in Pigs.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35464836","citation_count":12,"is_preprint":false},{"pmid":"15465120","id":"PMC_15465120","title":"The effect of unequal migration rates on FST.","date":"2004","source":"Theoretical population biology","url":"https://pubmed.ncbi.nlm.nih.gov/15465120","citation_count":9,"is_preprint":false},{"pmid":"36466321","id":"PMC_36466321","title":"Co-fermentation of non-Saccharomyces yeasts with Lactiplantibacillus plantarum FST 1.7 for the production of non-alcoholic beer.","date":"2022","source":"European food research and technology = Zeitschrift fur Lebensmittel-Untersuchung und -Forschung. A","url":"https://pubmed.ncbi.nlm.nih.gov/36466321","citation_count":8,"is_preprint":false},{"pmid":"35430886","id":"PMC_35430886","title":"Covariance of pairwise differences on a multi-species coalescent tree and implications for FST.","date":"2022","source":"Philosophical transactions of the Royal Society of London. Series B, Biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35430886","citation_count":8,"is_preprint":false},{"pmid":"35670225","id":"PMC_35670225","title":"Identification of genes associated with feather color in Liancheng white duck using FST analysis.","date":"2022","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35670225","citation_count":7,"is_preprint":false},{"pmid":"3898164","id":"PMC_3898164","title":"Feeding suppression induced by a fecal anorexigenic substance (FS-T).","date":"1985","source":"Physiology & behavior","url":"https://pubmed.ncbi.nlm.nih.gov/3898164","citation_count":7,"is_preprint":false},{"pmid":"33170076","id":"PMC_33170076","title":"Expression and polymorphism of Follistatin (FST) gene and its association with growth traits in native and exotic chicken.","date":"2020","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33170076","citation_count":6,"is_preprint":false},{"pmid":"30538303","id":"PMC_30538303","title":"FST between archaic and present-day samples.","date":"2018","source":"Heredity","url":"https://pubmed.ncbi.nlm.nih.gov/30538303","citation_count":6,"is_preprint":false},{"pmid":"37917549","id":"PMC_37917549","title":"Follistatin (FST) is expressed in buffalo (Bubalus bubalis) ovarian follicles and promotes oocyte maturation and early embryonic development.","date":"2023","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/37917549","citation_count":5,"is_preprint":false},{"pmid":"31285255","id":"PMC_31285255","title":"The Relationship Between Haplotype-Based F and Haplotype Length.","date":"2019","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31285255","citation_count":5,"is_preprint":false},{"pmid":"18845580","id":"PMC_18845580","title":"FABSIM: a software for generating FST distributions with various ascertainment biases.","date":"2008","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18845580","citation_count":5,"is_preprint":false},{"pmid":"39621755","id":"PMC_39621755","title":"FST and genetic diversity in an island model with background selection.","date":"2024","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39621755","citation_count":4,"is_preprint":false},{"pmid":"20186418","id":"PMC_20186418","title":"The distribution of Fst and other genetic statistics for a class of population structure models.","date":"2010","source":"Journal of mathematical biology","url":"https://pubmed.ncbi.nlm.nih.gov/20186418","citation_count":4,"is_preprint":false},{"pmid":"27565874","id":"PMC_27565874","title":"Expression, Regulation, and Functional Characterization of FST Gene in Porcine Granulosa Cells.","date":"2016","source":"Animal biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/27565874","citation_count":3,"is_preprint":false},{"pmid":"37153841","id":"PMC_37153841","title":"A Novel c.100C > G Mutation in the FST Gene and Its Relation With the Reproductive Traits of Awassi Ewes.","date":"2023","source":"Bioinformatics and biology insights","url":"https://pubmed.ncbi.nlm.nih.gov/37153841","citation_count":3,"is_preprint":false},{"pmid":"28768256","id":"PMC_28768256","title":"Estimation of FST and the Impact of de novo Mutation.","date":"2017","source":"Human heredity","url":"https://pubmed.ncbi.nlm.nih.gov/28768256","citation_count":3,"is_preprint":false},{"pmid":"23113792","id":"PMC_23113792","title":"Mutational analysis of the FST gene in Chinese women with idiopathic premature ovarian failure.","date":"2012","source":"Climacteric : the journal of the International Menopause Society","url":"https://pubmed.ncbi.nlm.nih.gov/23113792","citation_count":3,"is_preprint":false},{"pmid":"38109839","id":"PMC_38109839","title":"Synthesis and antibacterial activity of FST and its effects on inflammatory response and intestinal barrier function in mice infected with Escherichia coli O78.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38109839","citation_count":2,"is_preprint":false},{"pmid":"36893618","id":"PMC_36893618","title":"FST estimates of 94 populations in China based on STR markers.","date":"2023","source":"Forensic science international. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36893618","citation_count":2,"is_preprint":false},{"pmid":"41153936","id":"PMC_41153936","title":"Comparative Transcriptome Analysis Reveals the Role of the FST Gene in Goose Muscle Development.","date":"2025","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/41153936","citation_count":2,"is_preprint":false},{"pmid":"12669419","id":"PMC_12669419","title":"[Assessment of population differentiation using DNA fingerprinting and modified Wright's Fst-statistics].","date":"2003","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/12669419","citation_count":2,"is_preprint":false},{"pmid":"10634972","id":"PMC_10634972","title":"FST, a female-specific transcript from the medfly Ceratitis capitata (Diptera: Tephritidae).","date":"1999","source":"Insect molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10634972","citation_count":2,"is_preprint":false},{"pmid":"26186573","id":"PMC_26186573","title":"Mapping genetic determinants of viral traits with FST and quantitative trait locus (QTL) approaches.","date":"2015","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/26186573","citation_count":2,"is_preprint":false},{"pmid":"29718170","id":"PMC_29718170","title":"BlockFeST: Bayesian calculation of region-specific FST to detect local adaptation.","date":"2018","source":"Bioinformatics (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29718170","citation_count":2,"is_preprint":false},{"pmid":"9879018","id":"PMC_9879018","title":"[Selective structure of the gene pool. II. Standard method using F(ST) statistics].","date":"1998","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/9879018","citation_count":2,"is_preprint":false},{"pmid":"41147951","id":"PMC_41147951","title":"Location and Identity of Photoreceptors Contributing to the Full-Field Stimulus Test (FST).","date":"2025","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/41147951","citation_count":1,"is_preprint":false},{"pmid":"40725466","id":"PMC_40725466","title":"FST Polymorphisms Associate with Musculoskeletal Traits and Modulate Exercise Response Differentially by Sex and Modality in Northern Han Chinese Adults.","date":"2025","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/40725466","citation_count":1,"is_preprint":false},{"pmid":"9749343","id":"PMC_9749343","title":"[Interpopulation diversity of the gene pool: beta distribution of Wright's F(ST) statistics].","date":"1998","source":"Genetika","url":"https://pubmed.ncbi.nlm.nih.gov/9749343","citation_count":1,"is_preprint":false},{"pmid":"21798181","id":"PMC_21798181","title":"Interlocus variance of F(ST) provides evidence for directional selection over an olfactory receptor gene in Coho salmon (Oncorhynchus kisutch) populations.","date":"2009","source":"Marine genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21798181","citation_count":1,"is_preprint":false},{"pmid":"41565589","id":"PMC_41565589","title":"Integrated GWAS and Fst analysis identify flowering-time regulatory genes in maize.","date":"2026","source":"The plant genome","url":"https://pubmed.ncbi.nlm.nih.gov/41565589","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.17.688804","title":"Chronic cervical vibration ameliorates depression-like behavior in Wistar-Kyoto rats","date":"2025-11-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.688804","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.25.684561","title":"Is poor dose selection undermining the translational validity of antidepressant research involving animal models?","date":"2025-11-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.25.684561","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":33172,"output_tokens":1648,"usd":0.062118,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7932,"output_tokens":1614,"usd":0.040005,"stage2_stop_reason":"end_turn"},"total_usd":0.102123,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers about the human/mammalian FST gene (Follistatin). The corpus is heavily dominated by population genetics papers using FST as a statistical measure (fixation index), which are NOT about the FST gene/protein. I need to carefully filter for papers about the Follistatin protein (FST gene).\n\nRelevant papers about Follistatin (FST protein):\n- PMID:24667650 - ERRβ signaling through FST in breast cancer\n- PMID:23265961 - FST promoter methylation in PCOS (negative finding for methylation association)\n- PMID:28384189 - FST polymorphisms and wool traits in sheep\n- PMID:27565874 - FST in porcine granulosa cells\n- PMID:33170076 - FST expression in chicken\n- PMID:37917549 - FST in buffalo oocyte maturation\n- PMID:41153936 - FST in goose muscle development\n- PMID:23113792 - FST mutations in POF\n- PMID:37153841 - FST mutation in Awassi ewes\n\nThere are also papers about bacterial Fst toxin (different protein - from E. faecalis pAD1 plasmid) - these are NOT the human FST gene.\n\nPapers about the bacterial Fst toxin (PMID:16855226, 12644486, 20677831, 23104812, 28348028, 32722354) describe a completely different protein in bacteria - exclude.\n\nLet me extract only mechanistic discoveries about the mammalian Follistatin (FST) protein.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"ERRβ transcriptionally activates FST in breast cancer cells; chromatin immunoprecipitation identified FST as a direct ERRβ transcriptional target. Overexpressed ERRβ induced FST-mediated apoptosis and enhanced E-cadherin expression through FST upregulation. Additionally, ERRβ-mediated upregulation of BCAS2 inhibited FST transcription by downregulating β-catenin/TCF4 recruitment to the FST promoter.\",\n      \"method\": \"ChIP cloning, gel supershift assay, co-immunoprecipitation, western blotting, confocal microscopy, qRT-PCR\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and ChIP with multiple orthogonal methods in single lab; functional consequences (apoptosis, E-cadherin) measured but not independently replicated\",\n      \"pmids\": [\"24667650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FST is expressed in buffalo ovarian follicles at multiple stages and during oocyte maturation; FST overexpression promoted in vitro oocyte maturation rate and blastocyst development. FST knockdown in cumulus cells caused abnormal mitochondrial localization, reduced cumulus expansion, and decreased cleavage/blastocyst rates after parthenogenetic activation. Mechanistically, FST overexpression upregulated Bcl-2, TGF-β, SMAD2, and SMAD3 while downregulating SMAD4 and BAX, indicating FST acts through the TGF-β/SMAD pathway to regulate oocyte maturation and cumulus cell apoptosis.\",\n      \"method\": \"siRNA knockdown, overexpression vector (pcDNA3.1-EGFP-FST), RT-qPCR, immunostaining, mitochondrial localization assay, parthenogenetic activation assay\",\n      \"journal\": \"Reproduction in domestic animals\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) and gain-of-function with defined phenotypic readouts and pathway gene expression, single lab\",\n      \"pmids\": [\"37917549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FST mRNA levels decreased from weaning to estrus in porcine ovary, and FSH treatment (250 ng/ml) sharply decreased FST expression in porcine granulosa cells. Knockdown of FST by siRNA significantly increased granulosa cell proliferation and estrogen secretion, establishing FST as a negative regulator of follicle growth and granulosa cell function.\",\n      \"method\": \"siRNA knockdown, real-time PCR, cell proliferation assay, estrogen secretion measurement\",\n      \"journal\": \"Animal biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined cellular phenotypes (proliferation, estrogen secretion), single lab, single study\",\n      \"pmids\": [\"27565874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In goose skeletal muscle satellite cells (SMSCs), overexpression of FST downregulated stemness markers PAX7 and PAX3 and myogenic regulators (MYOG, MYOD, MYF5), while upregulating lipid metabolism genes (PPARG, FABP5, ACSL5) and myosin-related genes. Pathway analysis linked FST-regulated genes to TGF-β, PPAR, fatty acid metabolism, and Notch signaling pathways, indicating a dual regulatory role in skeletal muscle development and lipid metabolism.\",\n      \"method\": \"Overexpression in SMSCs, comparative transcriptome analysis (RNA-seq), qRT-PCR validation\",\n      \"journal\": \"Animals\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single overexpression experiment with transcriptome readout, no loss-of-function or protein-level mechanistic validation, single lab\",\n      \"pmids\": [\"41153936\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Follistatin (FST) is an activin-binding protein that functions as a negative regulator of follicle growth and granulosa cell function (suppressing proliferation and estrogen secretion); it is transcriptionally regulated by ERRβ (directly) and negatively by ERRβ-induced BCAS2 (via β-catenin/TCF4), promotes oocyte maturation and early embryonic development through the TGF-β/SMAD pathway, and modulates skeletal muscle development by suppressing myogenic regulatory factors while upregulating lipid metabolism genes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Follistatin (FST) acts as a negative regulator of ovarian follicle growth and granulosa cell function, where its knockdown increases granulosa cell proliferation and estrogen secretion and FSH treatment sharply downregulates its expression [#2]. In oocytes and cumulus cells, FST promotes in vitro oocyte maturation, cumulus expansion, and early embryonic (blastocyst) development, acting through the TGF-\\u03b2/SMAD pathway by upregulating TGF-\\u03b2, SMAD2, SMAD3, and the anti-apoptotic factor Bcl-2 while downregulating SMAD4 and BAX [#1]. FST transcription is directly activated by ERR\\u03b2, which binds the FST promoter and drives FST-mediated apoptosis and E-cadherin upregulation in breast cancer cells; ERR\\u03b2 also indirectly represses FST via BCAS2-dependent downregulation of \\u03b2-catenin/TCF4 recruitment to the FST promoter [#0]. Beyond reproductive and transcriptional contexts, FST overexpression suppresses myogenic regulators (PAX7, PAX3, MYOG, MYOD, MYF5) while inducing lipid-metabolism genes, linking it to muscle development and lipid handling [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Established how FST expression is controlled at the transcriptional level, identifying FST as a direct ERR\\u03b2 target with both positive and indirect negative regulatory arms.\",\n      \"evidence\": \"ChIP cloning, gel supershift, Co-IP, and qRT-PCR in breast cancer cells\",\n      \"pmids\": [\"24667650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences (apoptosis, E-cadherin) measured in a single lab without independent replication\", \"Does not address FST's secreted ligand-binding activity\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined FST as a negative regulator of follicle growth, showing it restrains granulosa cell proliferation and estrogen output downstream of FSH.\",\n      \"evidence\": \"siRNA knockdown with proliferation and estrogen secretion assays in porcine granulosa cells\",\n      \"pmids\": [\"27565874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single study, single species\", \"Molecular mechanism linking FST loss to proliferation not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected FST to oocyte maturation and early embryo development, placing its action within the TGF-\\u03b2/SMAD pathway and cumulus cell survival.\",\n      \"evidence\": \"siRNA knockdown and overexpression with maturation, mitochondrial localization, and parthenogenetic activation assays in buffalo follicles\",\n      \"pmids\": [\"37917549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway inference rests on expression of SMAD genes, not direct SMAD activation readouts\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended FST function beyond reproduction, implicating it in suppressing myogenic differentiation while promoting lipid metabolism in muscle satellite cells.\",\n      \"evidence\": \"Overexpression with RNA-seq and qRT-PCR validation in goose skeletal muscle satellite cells\",\n      \"pmids\": [\"41153936\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single overexpression experiment with no loss-of-function\", \"No protein-level mechanistic validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular activity of FST as a secreted binding protein (e.g. its ligand targets and binding mechanism) is not characterized in the available corpus.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural or biochemical binding data in timeline\", \"Cross-tissue mechanism (reproduction vs muscle) not unified by direct experiment\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}