{"gene":"H2AC4","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2023,"finding":"HIST1H2AB (H2AC4) knockdown inhibited proliferation and promoted apoptosis of lung adenocarcinoma cells (A549 and H1299) in vitro and delayed tumor growth in xenograft models. Gene expression array analysis suggested that HIST1H2AB regulates the interferon signaling pathway and genes including HMGB1, FOXM1, F2RL1, and SLC4A7 in lung adenocarcinoma.","method":"shRNA-mediated knockdown, colony formation assay, Annexin V apoptosis assay, xenograft mouse model, human gene expression array, RT-qPCR, western blotting","journal":"The journal of gene medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype (proliferation, apoptosis) confirmed in vivo, plus gene expression profiling; single lab, no reconstitution or structure","pmids":["36511295"],"is_preprint":false}],"current_model":"H2AC4 (HIST1H2AB) is a histone H2A family member whose knockdown suppresses lung adenocarcinoma cell proliferation and promotes apoptosis, with evidence suggesting it regulates the interferon signaling pathway and downstream genes (HMGB1, FOXM1, F2RL1, SLC4A7); beyond this oncogenic role in lung cancer, no detailed molecular mechanism for the canonical H2AC4 protein has been established in the available literature."},"narrative":{"mechanistic_narrative":"H2AC4 (HIST1H2AB), a histone H2A family member, has been characterized in the available corpus primarily through its role in lung adenocarcinoma, where its knockdown inhibits proliferation, promotes apoptosis, and delays xenograft tumor growth [PMID:36511295]. Gene expression profiling links H2AC4 to regulation of the interferon signaling pathway and downstream genes including HMGB1, FOXM1, F2RL1, and SLC4A7 [PMID:36511295]. Beyond this oncogenic association, no detailed molecular mechanism for the canonical H2AC4 protein has been established in the available corpus.","teleology":[{"year":2023,"claim":"Whether H2AC4 contributes functionally to cancer was unknown; loss-of-function established it as a pro-proliferative, anti-apoptotic factor in lung adenocarcinoma and tied it to interferon-pathway gene regulation.","evidence":"shRNA knockdown with colony formation and Annexin V apoptosis assays in A549 and H1299 cells, xenograft mouse model, and gene expression array with RT-qPCR/western validation","pmids":["36511295"],"confidence":"Medium","gaps":["No direct biochemical mechanism linking the histone to interferon-pathway or HMGB1/FOXM1/F2RL1/SLC4A7 regulation","Single lab, no reconstitution or rescue of the knockdown phenotype","No structural or chromatin-level characterization of the canonical protein"]},{"year":null,"claim":"The molecular function of H2AC4 as a nucleosomal histone and the mechanism by which its levels influence the interferon signaling axis remain uncharacterized.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct evidence that H2AC4 incorporation into chromatin drives the observed transcriptional changes","No interaction partners or post-translational modifications defined in the corpus"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P04908","full_name":"Histone H2A type 1-B/E","aliases":["Histone H2A.2","Histone H2A/a","Histone H2A/m"],"length_aa":130,"mass_kda":14.1,"function":"Core component of nucleosome. 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DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/P04908/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/H2AC4","classification":"Common Essential","n_dependent_lines":584,"n_total_lines":1208,"dependency_fraction":0.48344370860927155},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PPM1G","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/H2AC4","total_profiled":1310},"omim":[{"mim_id":"602795","title":"HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER B; HIST1H2AB","url":"https://www.omim.org/entry/602795"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in single","driving_tissues":[{"tissue":"bone marrow","ntpm":1.4}],"url":"https://www.proteinatlas.org/search/H2AC4"},"hgnc":{"alias_symbol":["H2A/m"],"prev_symbol":["H2AFM","HIST1H2AB"]},"alphafold":{"accession":"P04908","domains":[{"cath_id":"1.10.20.10","chopping":"18-109","consensus_level":"medium","plddt":97.7555,"start":18,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P04908","model_url":"https://alphafold.ebi.ac.uk/files/AF-P04908-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P04908-F1-predicted_aligned_error_v6.png","plddt_mean":90.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H2AC4","jax_strain_url":"https://www.jax.org/strain/search?query=H2AC4"},"sequence":{"accession":"P04908","fasta_url":"https://rest.uniprot.org/uniprotkb/P04908.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P04908/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P04908"}},"corpus_meta":[{"pmid":"15073169","id":"PMC_15073169","title":"Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15073169","citation_count":307,"is_preprint":false},{"pmid":"33438329","id":"PMC_33438329","title":"Dynamic transcriptomic m5 C and its regulatory role in RNA processing.","date":"2021","source":"Wiley interdisciplinary reviews. 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Gene expression array analysis suggested that HIST1H2AB regulates the interferon signaling pathway and genes including HMGB1, FOXM1, F2RL1, and SLC4A7 in lung adenocarcinoma.\",\n      \"method\": \"shRNA-mediated knockdown, colony formation assay, Annexin V apoptosis assay, xenograft mouse model, human gene expression array, RT-qPCR, western blotting\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype (proliferation, apoptosis) confirmed in vivo, plus gene expression profiling; single lab, no reconstitution or structure\",\n      \"pmids\": [\"36511295\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"H2AC4 (HIST1H2AB) is a histone H2A family member whose knockdown suppresses lung adenocarcinoma cell proliferation and promotes apoptosis, with evidence suggesting it regulates the interferon signaling pathway and downstream genes (HMGB1, FOXM1, F2RL1, SLC4A7); beyond this oncogenic role in lung cancer, no detailed molecular mechanism for the canonical H2AC4 protein has been established in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H2AC4 (HIST1H2AB), a histone H2A family member, has been characterized in the available corpus primarily through its role in lung adenocarcinoma, where its knockdown inhibits proliferation, promotes apoptosis, and delays xenograft tumor growth [#0]. Gene expression profiling links H2AC4 to regulation of the interferon signaling pathway and downstream genes including HMGB1, FOXM1, F2RL1, and SLC4A7 [#0]. Beyond this oncogenic association, no detailed molecular mechanism for the canonical H2AC4 protein has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether H2AC4 contributes functionally to cancer was unknown; loss-of-function established it as a pro-proliferative, anti-apoptotic factor in lung adenocarcinoma and tied it to interferon-pathway gene regulation.\",\n      \"evidence\": \"shRNA knockdown with colony formation and Annexin V apoptosis assays in A549 and H1299 cells, xenograft mouse model, and gene expression array with RT-qPCR/western validation\",\n      \"pmids\": [\"36511295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct biochemical mechanism linking the histone to interferon-pathway or HMGB1/FOXM1/F2RL1/SLC4A7 regulation\",\n        \"Single lab, no reconstitution or rescue of the knockdown phenotype\",\n        \"No structural or chromatin-level characterization of the canonical protein\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular function of H2AC4 as a nucleosomal histone and the mechanism by which its levels influence the interferon signaling axis remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct evidence that H2AC4 incorporation into chromatin drives the observed transcriptional changes\",\n        \"No interaction partners or post-translational modifications defined in the corpus\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":2,"faith_total":2,"faith_pct":100.0}}