{"gene":"ANKRD37","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2009,"finding":"ANKRD37 is a direct transcriptional target of HIF-1 (Hypoxia-Inducible Factor-1). Experimental validation using an integrative genomics approach combining microarray data and promoter analysis for conserved HIF-1-binding sites confirmed ANKRD37 as a novel HIF-1 target gene.","method":"Integrative genomics: microarray differential expression analysis combined with computational HIF-1 binding site scoring and experimental validation","journal":"Nucleic Acids Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — computational prediction plus experimental validation in a single study, but abstract does not detail the exact experimental method (e.g., ChIP, reporter assay) used for validation","pmids":["19491311"],"is_preprint":false},{"year":2011,"finding":"Ankrd37 protein contains ankyrin repeats and a putative nuclear localization signal (NLS), is present in the cytoplasm of elongating spermatids and later restricted to nuclei of spermatozoa during mouse spermatogenesis. Ankrd37 binds to Fem1b (feminization 1 homolog b) as shown by yeast two-hybrid screening and co-immunoprecipitation. Ankrd37 facilitates transport of Fem1b from cytoplasm to nucleus in co-transfected CHO cells. Fem1b targets Ankrd37 for ubiquitin-mediated degradation in a dose-dependent manner.","method":"Yeast two-hybrid screening, co-immunoprecipitation, co-transfection with immunofluorescence localization, ubiquitination assay","journal":"Gene","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, functional localization, and ubiquitination assay, multiple orthogonal methods in one study","pmids":["21723927"],"is_preprint":false},{"year":2020,"finding":"In colon cancer cells (RKO line), hypoxia-induced HIF-1α upregulates ANKRD37, and intranuclear ANKRD37 plays a required role in regulating hypoxia-induced autophagy and promoting cell growth. Translocation of ANKRD37 into the cell nucleus is necessary for these effects.","method":"RNA interference (siRNA knockdown), immunoblot, immunofluorescence in cancer cell lines under hypoxic conditions","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (autophagy), localization tied to functional consequence, single lab with multiple orthogonal methods","pmids":["32679233"],"is_preprint":false},{"year":2022,"finding":"ANKRD37 overexpression in mouse hippocampus reduces hippocampal volume. A causal chain was established: rs1053218 SNP mutation causes cg26741686 hypermethylation, which leads to ANKRD37 overexpression, which reduces hippocampal volume. This was confirmed by CRISPR-based genome and epigenome editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and by ANKRD37 overexpression in mouse hippocampus in vivo.","method":"CRISPR genome/epigenome editing, overexpression in mouse hippocampus in vivo, cross-omics analysis (SNP, methylation, transcriptome, neuroimaging)","journal":"Molecular Psychiatry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR-based editing with in vivo overexpression, replicated in independent cohorts, multiple orthogonal methods","pmids":["36195640"],"is_preprint":false},{"year":2022,"finding":"ANKRD37 knockdown in trophoblast cell lines (HTR8/SVneo and JEG-3) enhances trophoblast migration and invasion and promotes extravillous explant outgrowth, while ANKRD37 overexpression has the opposite effects. RNA sequencing indicated NF-κB as a downstream pathway of ANKRD37, confirmed by changes in p-p65 and p-IκBα expression, suggesting ANKRD37 inhibits trophoblast migration/invasion via the NF-κB pathway.","method":"siRNA knockdown, overexpression, wound healing assay, Transwell invasion assay, extravillous explant culture, RNA sequencing, Western blotting (p-p65, p-IκBα)","journal":"The Journal of Gene Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and pathway placement via RNA-seq and protein markers, single lab","pmids":["35218282"],"is_preprint":false},{"year":2017,"finding":"ANKRD37 mRNA expression is regulated by iron status in intestinal (Caco-2) and liver (HepG2) cell lines; iron deficiency induces ANKRD37 mRNA, and iron supplementation (via ABS-derived iron or ferric ammonium citrate) reduces it. ANKRD37 functions as a marker gene for iron-deficiency anemia.","method":"Quantitative RT-PCR in Caco-2 and HepG2 cells treated with deferoxamine-induced iron deficiency and iron supplementation","journal":"Clinical and Applied Thrombosis/Hemostasis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (qRT-PCR), no mechanistic follow-up beyond mRNA expression measurement","pmids":["29110513"],"is_preprint":false}],"current_model":"ANKRD37 is a direct HIF-1 transcriptional target gene whose protein product contains ankyrin repeats and a nuclear localization signal; it undergoes nuclear translocation where it promotes hypoxia-induced autophagy and cell growth, is ubiquitinated and degraded via Fem1b interaction, and in trophoblasts suppresses migration and invasion through the NF-κB pathway, while in the hippocampus its overexpression (causally linked to a DNA methylation QTL) reduces hippocampal volume."},"narrative":{"mechanistic_narrative":"ANKRD37 is a hypoxia-responsive ankyrin-repeat protein that acts as a direct HIF-1 transcriptional target and contributes to the cellular response to low oxygen [PMID:19491311, PMID:32679233]. Its protein product carries ankyrin repeats and a nuclear localization signal, and nuclear translocation of ANKRD37 is required for its activity: in colon cancer cells, HIF-1α-driven ANKRD37 promotes hypoxia-induced autophagy and cell growth [PMID:32679233]. ANKRD37 binds Fem1b, facilitates Fem1b's cytoplasm-to-nucleus transport, and is itself targeted by Fem1b for ubiquitin-mediated degradation, placing it within a reciprocal regulatory partnership [PMID:21723927]. Beyond hypoxia, ANKRD37 restrains trophoblast migration and invasion through the NF-κB pathway, acting on p65 and IκBα phosphorylation [PMID:35218282], and its overexpression in mouse hippocampus reduces hippocampal volume via a causal chain originating from a methylation QTL [PMID:36195640].","teleology":[{"year":2009,"claim":"Established ANKRD37 as a transcriptional output of hypoxia signaling, defining its primary regulatory context as a HIF-1 target gene.","evidence":"Integrative genomics combining microarray expression with HIF-1 binding-site scoring and experimental validation","pmids":["19491311"],"confidence":"Medium","gaps":["Exact validation method (ChIP vs reporter) not detailed","No functional consequence of the induction tested in this study","Tissue/context specificity of HIF-1 regulation not defined"]},{"year":2011,"claim":"Defined ANKRD37 at the protein level as an ankyrin-repeat, NLS-bearing protein and identified Fem1b as a direct partner that both is escorted to the nucleus by ANKRD37 and targets ANKRD37 for ubiquitin-mediated degradation.","evidence":"Yeast two-hybrid, reciprocal co-immunoprecipitation, co-transfection immunofluorescence, and ubiquitination assays during mouse spermatogenesis and in CHO cells","pmids":["21723927"],"confidence":"High","gaps":["Functional outcome of the ANKRD37-Fem1b axis in spermatogenesis not established","Whether Fem1b degradation links to hypoxia signaling untested","E3 ligase identity / degradation pathway details not resolved"]},{"year":2020,"claim":"Connected ANKRD37 induction to a concrete cellular phenotype, showing nuclear ANKRD37 is required for hypoxia-induced autophagy and cell growth.","evidence":"siRNA knockdown with immunoblot and immunofluorescence in hypoxic RKO colon cancer cells","pmids":["32679233"],"confidence":"Medium","gaps":["Molecular mechanism linking nuclear ANKRD37 to autophagy machinery unknown","Direct nuclear targets or binding partners mediating the effect not identified","Single cell line / single lab"]},{"year":2022,"claim":"Showed ANKRD37 suppresses trophoblast migration and invasion, placing NF-κB downstream of its activity.","evidence":"Knockdown and overexpression with wound-healing, Transwell, explant outgrowth assays, RNA-seq, and Western blot for p-p65/p-IκBα in HTR8/SVneo and JEG-3 cells","pmids":["35218282"],"confidence":"Medium","gaps":["Direct mechanism by which ANKRD37 engages NF-κB signaling not defined","Relationship to hypoxia/HIF-1 axis in trophoblasts not tested","Single lab"]},{"year":2022,"claim":"Established a causal genotype-to-phenotype chain whereby ANKRD37 overexpression reduces hippocampal volume.","evidence":"CRISPR genome/epigenome editing of rs1053218 and cg26741686, in vivo hippocampal overexpression, and cross-omics neuroimaging analysis","pmids":["36195640"],"confidence":"High","gaps":["Molecular mechanism by which ANKRD37 affects hippocampal volume unknown","Whether HIF-1/Fem1b/NF-κB axes are involved in the neural phenotype untested"]},{"year":null,"claim":"The unifying molecular function of nuclear ANKRD37 — how its ankyrin repeats and Fem1b interaction mechanistically drive autophagy, NF-κB modulation, and tissue-specific phenotypes — remains undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No biochemical activity assigned to the ankyrin-repeat protein","No structural model or defined nuclear effector targets","Iron-status regulation (#5) not connected mechanistically to other functions"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2]}],"complexes":[],"partners":["FEM1B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z713","full_name":"Ankyrin repeat domain-containing protein 37","aliases":["Low-density lipoprotein receptor-related protein 2-binding protein","hLrp2bp"],"length_aa":158,"mass_kda":16.9,"function":"","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q7Z713/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANKRD37","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANKRD37","total_profiled":1310},"omim":[{"mim_id":"619021","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 37; ANKRD37","url":"https://www.omim.org/entry/619021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ANKRD37"},"hgnc":{"alias_symbol":["Lrp2bp"],"prev_symbol":[]},"alphafold":{"accession":"Q7Z713","domains":[{"cath_id":"1.25.40.20","chopping":"10-22_29-125","consensus_level":"high","plddt":87.0926,"start":10,"end":125}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z713","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z713-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z713-F1-predicted_aligned_error_v6.png","plddt_mean":72.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANKRD37","jax_strain_url":"https://www.jax.org/strain/search?query=ANKRD37"},"sequence":{"accession":"Q7Z713","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z713.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z713/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z713"}},"corpus_meta":[{"pmid":"19491311","id":"PMC_19491311","title":"An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1)-target genes that form the core response to hypoxia.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19491311","citation_count":390,"is_preprint":false},{"pmid":"24842922","id":"PMC_24842922","title":"Elevated testosterone levels during rat pregnancy cause hypersensitivity to angiotensin II and attenuation of endothelium-dependent vasodilation in uterine arteries.","date":"2014","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/24842922","citation_count":58,"is_preprint":false},{"pmid":"32679233","id":"PMC_32679233","title":"HIF-1a regulates hypoxia-induced autophagy via translocation of ANKRD37 in colon cancer.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32679233","citation_count":41,"is_preprint":false},{"pmid":"25093114","id":"PMC_25093114","title":"Analysis of the placental tissue transcriptome of normal and preeclampsia complicated pregnancies.","date":"2014","source":"Acta naturae","url":"https://pubmed.ncbi.nlm.nih.gov/25093114","citation_count":29,"is_preprint":false},{"pmid":"25715653","id":"PMC_25715653","title":"Genome-Wide Profiling of TRACK Kidneys Shows Similarity to the Human ccRCC Transcriptome.","date":"2015","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/25715653","citation_count":22,"is_preprint":false},{"pmid":"21723927","id":"PMC_21723927","title":"Mouse Fem1b interacts with and induces ubiquitin-mediated degradation of Ankrd37.","date":"2011","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/21723927","citation_count":20,"is_preprint":false},{"pmid":"29783732","id":"PMC_29783732","title":"Hyaluronic Acid Influence on Normal and Osteoarthritic Tissue-Engineered Cartilage.","date":"2018","source":"International journal of molecular 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health","url":"https://pubmed.ncbi.nlm.nih.gov/36901532","citation_count":11,"is_preprint":false},{"pmid":"27005936","id":"PMC_27005936","title":"Relaxin deficiency results in increased expression of angiogenesis- and remodelling-related genes in the uterus of early pregnant mice but does not affect endometrial angiogenesis prior to implantation.","date":"2016","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/27005936","citation_count":11,"is_preprint":false},{"pmid":"38899809","id":"PMC_38899809","title":"Combined analysis of the effects of hypoxia and oxidative stress on DNA methylation and the transcriptome in HTR-8/SVneo trophoblast cells.","date":"2024","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38899809","citation_count":9,"is_preprint":false},{"pmid":"38894741","id":"PMC_38894741","title":"Unveiling immune tolerance pathways in preeclampsia placenta: implications for molecular 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protein degradation in M. gastrocnemius of 24-day-old mice by activating FOXO1 and suppressing AKT-mTORC1.","date":"2025","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40094441","citation_count":6,"is_preprint":false},{"pmid":"29110513","id":"PMC_29110513","title":"Ankaferd Influences mRNA Expression of Iron-Regulated Genes During Iron-Deficiency Anemia.","date":"2017","source":"Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis","url":"https://pubmed.ncbi.nlm.nih.gov/29110513","citation_count":6,"is_preprint":false},{"pmid":"35158722","id":"PMC_35158722","title":"Comparison of lncRNA Expression in the Uterus between Periods of Embryo Implantation and Labor in Mice.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/35158722","citation_count":5,"is_preprint":false},{"pmid":"40119318","id":"PMC_40119318","title":"NDRG1 alleviates Erastin-induced ferroptosis of hepatocellular carcinoma.","date":"2025","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40119318","citation_count":4,"is_preprint":false},{"pmid":"36494833","id":"PMC_36494833","title":"Comparison of apical and basolateral Cu treatment for iron-related gene regulation during deferoxamine induced iron deficiency.","date":"2022","source":"Genes & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/36494833","citation_count":3,"is_preprint":false},{"pmid":"39596293","id":"PMC_39596293","title":"Molecules That Have Rarely Been Studied in Lymphatic Endothelial Cells.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39596293","citation_count":2,"is_preprint":false},{"pmid":"40715562","id":"PMC_40715562","title":"CRP and HNF1A collaborate to regulate the progression of laryngeal cancer through the Wnt signaling pathway.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40715562","citation_count":2,"is_preprint":false},{"pmid":"19171189","id":"PMC_19171189","title":"WITHDRAWN: Fem1b interacts with Ankrd37 in mouse testis and induces its degradation by ubiquitin-mediated proteolysis pathway.","date":"2009","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/19171189","citation_count":0,"is_preprint":false},{"pmid":"40770382","id":"PMC_40770382","title":"Giardia duodenalis stabilizes HIF-1α and induces glycolytic alterations in intestinal epithelial cells.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40770382","citation_count":0,"is_preprint":false},{"pmid":"41729213","id":"PMC_41729213","title":"Integrated single-cell multi-omics analysis unveils heterogeneity in the prostate cancer tumor microenvironment.","date":"2026","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41729213","citation_count":0,"is_preprint":false},{"pmid":"41621311","id":"PMC_41621311","title":"FTIR spectroscopy coupled with chemometrics for evaluating functional food efficacy in an in vitro model of iron deficiency anemia.","date":"2026","source":"Food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41621311","citation_count":0,"is_preprint":false},{"pmid":"41234107","id":"PMC_41234107","title":"[Comparative Study of Diffuse Large B-Cell Lymphoma and Reactive Lymphoid Hyperplasia Lymph Node Derived Mesenchymal Stem Cells].","date":"2025","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/41234107","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15872,"output_tokens":1719,"usd":0.0367,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8603,"output_tokens":2237,"usd":0.04947,"stage2_stop_reason":"end_turn"},"total_usd":0.08617,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2009,\n      \"finding\": \"ANKRD37 is a direct transcriptional target of HIF-1 (Hypoxia-Inducible Factor-1). Experimental validation using an integrative genomics approach combining microarray data and promoter analysis for conserved HIF-1-binding sites confirmed ANKRD37 as a novel HIF-1 target gene.\",\n      \"method\": \"Integrative genomics: microarray differential expression analysis combined with computational HIF-1 binding site scoring and experimental validation\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — computational prediction plus experimental validation in a single study, but abstract does not detail the exact experimental method (e.g., ChIP, reporter assay) used for validation\",\n      \"pmids\": [\"19491311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ankrd37 protein contains ankyrin repeats and a putative nuclear localization signal (NLS), is present in the cytoplasm of elongating spermatids and later restricted to nuclei of spermatozoa during mouse spermatogenesis. Ankrd37 binds to Fem1b (feminization 1 homolog b) as shown by yeast two-hybrid screening and co-immunoprecipitation. Ankrd37 facilitates transport of Fem1b from cytoplasm to nucleus in co-transfected CHO cells. Fem1b targets Ankrd37 for ubiquitin-mediated degradation in a dose-dependent manner.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, co-transfection with immunofluorescence localization, ubiquitination assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, yeast two-hybrid, functional localization, and ubiquitination assay, multiple orthogonal methods in one study\",\n      \"pmids\": [\"21723927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In colon cancer cells (RKO line), hypoxia-induced HIF-1α upregulates ANKRD37, and intranuclear ANKRD37 plays a required role in regulating hypoxia-induced autophagy and promoting cell growth. Translocation of ANKRD37 into the cell nucleus is necessary for these effects.\",\n      \"method\": \"RNA interference (siRNA knockdown), immunoblot, immunofluorescence in cancer cell lines under hypoxic conditions\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (autophagy), localization tied to functional consequence, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32679233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANKRD37 overexpression in mouse hippocampus reduces hippocampal volume. A causal chain was established: rs1053218 SNP mutation causes cg26741686 hypermethylation, which leads to ANKRD37 overexpression, which reduces hippocampal volume. This was confirmed by CRISPR-based genome and epigenome editing of rs1053218 homologous alleles and cg26741686 methylation in mouse neural stem cell differentiation models, and by ANKRD37 overexpression in mouse hippocampus in vivo.\",\n      \"method\": \"CRISPR genome/epigenome editing, overexpression in mouse hippocampus in vivo, cross-omics analysis (SNP, methylation, transcriptome, neuroimaging)\",\n      \"journal\": \"Molecular Psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR-based editing with in vivo overexpression, replicated in independent cohorts, multiple orthogonal methods\",\n      \"pmids\": [\"36195640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ANKRD37 knockdown in trophoblast cell lines (HTR8/SVneo and JEG-3) enhances trophoblast migration and invasion and promotes extravillous explant outgrowth, while ANKRD37 overexpression has the opposite effects. RNA sequencing indicated NF-κB as a downstream pathway of ANKRD37, confirmed by changes in p-p65 and p-IκBα expression, suggesting ANKRD37 inhibits trophoblast migration/invasion via the NF-κB pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, wound healing assay, Transwell invasion assay, extravillous explant culture, RNA sequencing, Western blotting (p-p65, p-IκBα)\",\n      \"journal\": \"The Journal of Gene Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined cellular phenotype and pathway placement via RNA-seq and protein markers, single lab\",\n      \"pmids\": [\"35218282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANKRD37 mRNA expression is regulated by iron status in intestinal (Caco-2) and liver (HepG2) cell lines; iron deficiency induces ANKRD37 mRNA, and iron supplementation (via ABS-derived iron or ferric ammonium citrate) reduces it. ANKRD37 functions as a marker gene for iron-deficiency anemia.\",\n      \"method\": \"Quantitative RT-PCR in Caco-2 and HepG2 cells treated with deferoxamine-induced iron deficiency and iron supplementation\",\n      \"journal\": \"Clinical and Applied Thrombosis/Hemostasis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (qRT-PCR), no mechanistic follow-up beyond mRNA expression measurement\",\n      \"pmids\": [\"29110513\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANKRD37 is a direct HIF-1 transcriptional target gene whose protein product contains ankyrin repeats and a nuclear localization signal; it undergoes nuclear translocation where it promotes hypoxia-induced autophagy and cell growth, is ubiquitinated and degraded via Fem1b interaction, and in trophoblasts suppresses migration and invasion through the NF-κB pathway, while in the hippocampus its overexpression (causally linked to a DNA methylation QTL) reduces hippocampal volume.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANKRD37 is a hypoxia-responsive ankyrin-repeat protein that acts as a direct HIF-1 transcriptional target and contributes to the cellular response to low oxygen [#0, #2]. Its protein product carries ankyrin repeats and a nuclear localization signal, and nuclear translocation of ANKRD37 is required for its activity: in colon cancer cells, HIF-1\\u03b1-driven ANKRD37 promotes hypoxia-induced autophagy and cell growth [#2]. ANKRD37 binds Fem1b, facilitates Fem1b's cytoplasm-to-nucleus transport, and is itself targeted by Fem1b for ubiquitin-mediated degradation, placing it within a reciprocal regulatory partnership [#1]. Beyond hypoxia, ANKRD37 restrains trophoblast migration and invasion through the NF-\\u03baB pathway, acting on p65 and I\\u03baB\\u03b1 phosphorylation [#4], and its overexpression in mouse hippocampus reduces hippocampal volume via a causal chain originating from a methylation QTL [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established ANKRD37 as a transcriptional output of hypoxia signaling, defining its primary regulatory context as a HIF-1 target gene.\",\n      \"evidence\": \"Integrative genomics combining microarray expression with HIF-1 binding-site scoring and experimental validation\",\n      \"pmids\": [\"19491311\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Exact validation method (ChIP vs reporter) not detailed\",\n        \"No functional consequence of the induction tested in this study\",\n        \"Tissue/context specificity of HIF-1 regulation not defined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined ANKRD37 at the protein level as an ankyrin-repeat, NLS-bearing protein and identified Fem1b as a direct partner that both is escorted to the nucleus by ANKRD37 and targets ANKRD37 for ubiquitin-mediated degradation.\",\n      \"evidence\": \"Yeast two-hybrid, reciprocal co-immunoprecipitation, co-transfection immunofluorescence, and ubiquitination assays during mouse spermatogenesis and in CHO cells\",\n      \"pmids\": [\"21723927\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional outcome of the ANKRD37-Fem1b axis in spermatogenesis not established\",\n        \"Whether Fem1b degradation links to hypoxia signaling untested\",\n        \"E3 ligase identity / degradation pathway details not resolved\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected ANKRD37 induction to a concrete cellular phenotype, showing nuclear ANKRD37 is required for hypoxia-induced autophagy and cell growth.\",\n      \"evidence\": \"siRNA knockdown with immunoblot and immunofluorescence in hypoxic RKO colon cancer cells\",\n      \"pmids\": [\"32679233\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism linking nuclear ANKRD37 to autophagy machinery unknown\",\n        \"Direct nuclear targets or binding partners mediating the effect not identified\",\n        \"Single cell line / single lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ANKRD37 suppresses trophoblast migration and invasion, placing NF-\\u03baB downstream of its activity.\",\n      \"evidence\": \"Knockdown and overexpression with wound-healing, Transwell, explant outgrowth assays, RNA-seq, and Western blot for p-p65/p-I\\u03baB\\u03b1 in HTR8/SVneo and JEG-3 cells\",\n      \"pmids\": [\"35218282\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Direct mechanism by which ANKRD37 engages NF-\\u03baB signaling not defined\",\n        \"Relationship to hypoxia/HIF-1 axis in trophoblasts not tested\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a causal genotype-to-phenotype chain whereby ANKRD37 overexpression reduces hippocampal volume.\",\n      \"evidence\": \"CRISPR genome/epigenome editing of rs1053218 and cg26741686, in vivo hippocampal overexpression, and cross-omics neuroimaging analysis\",\n      \"pmids\": [\"36195640\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism by which ANKRD37 affects hippocampal volume unknown\",\n        \"Whether HIF-1/Fem1b/NF-\\u03baB axes are involved in the neural phenotype untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular function of nuclear ANKRD37 — how its ankyrin repeats and Fem1b interaction mechanistically drive autophagy, NF-\\u03baB modulation, and tissue-specific phenotypes — remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No biochemical activity assigned to the ankyrin-repeat protein\",\n        \"No structural model or defined nuclear effector targets\",\n        \"Iron-status regulation (#5) not connected mechanistically to other functions\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FEM1B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":4,"faith_pct":75.0}}