{"gene":"H2AC20","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2017,"finding":"The canonical histone H2A isoform Hist2h2ac (HIST2H2AC/H2AC20) is expressed specifically in undifferentiated/proliferating mammary epithelial cells and is downstream of EGF/EGFR signaling via MEK1/2 and PI3-K pathways. Silencing of Hist2h2ac inhibited EGF-induced Zeb-1 expression and prevented E-cadherin downregulation (epithelial-mesenchymal transition markers), an effect rescued by Hist2h2ac re-expression. Knockdown also blocked EGF-induced proliferation despite increased EGFR/ERBB2/ERK1/2 activation, placing Hist2h2ac downstream of EGFR signaling and as a regulator of oncogenic EMT and proliferation programs.","method":"Mass spectrometry screening of histone levels during differentiation; siRNA-mediated silencing; re-expression rescue; qRT-PCR; Western blot; cell proliferation assays in HC11, EpH4, MC4-L2, and T47-D cell lines","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, multiple orthogonal methods (MS identification, siRNA knockdown, rescue, proliferation assay), clean loss-of-function with defined phenotypic readouts and pathway placement downstream of EGFR","pmids":["28288875"],"is_preprint":false}],"current_model":"Hist2h2ac (H2AC20/HIST2H2AC), a canonical H2A histone isoform, is expressed in proliferating/undifferentiated mammary epithelial cells downstream of EGFR-MEK/PI3K signaling, where it promotes EGF-induced cell proliferation and epithelial-mesenchymal transition by supporting Zeb-1 expression and E-cadherin downregulation; beyond this, no further mechanistic findings specific to this isoform (as distinct from other H2A variants) are established in the available literature."},"narrative":{"mechanistic_narrative":"H2AC20 (Hist2h2ac/HIST2H2AC) is a canonical histone H2A isoform whose expression marks undifferentiated, proliferating mammary epithelial cells and operates as a downstream effector of EGF/EGFR signaling acting through the MEK1/2 and PI3-K pathways [PMID:28288875]. Silencing of Hist2h2ac blocks EGF-induced Zeb-1 expression and prevents E-cadherin downregulation, and re-expression rescues these defects, placing this isoform within the epithelial-mesenchymal transition program; its knockdown also abolishes EGF-induced proliferation despite intact upstream EGFR/ERBB2/ERK1/2 activation, indicating it acts downstream of receptor signaling to drive proliferation and EMT [PMID:28288875]. Beyond this single characterization in mammary epithelial cells, no further mechanism specific to this H2A isoform has been established in the available corpus.","teleology":[{"year":2017,"claim":"Established that a specific canonical H2A isoform, rather than H2A variants generally, is selectively expressed in proliferating mammary epithelial cells and functions as a downstream effector of EGFR signaling driving EMT and proliferation.","evidence":"Mass spectrometry of histone levels during differentiation, siRNA silencing with re-expression rescue, and proliferation/EMT marker assays across HC11, EpH4, MC4-L2, and T47-D cell lines","pmids":["28288875"],"confidence":"Medium","gaps":["No molecular mechanism by which a canonical histone isoform selectively controls Zeb-1/E-cadherin transcription is defined","Whether the phenotype reflects isoform-specific chromatin incorporation versus a non-canonical function is not resolved","Findings come from a single lab and cultured cell lines without in vivo validation"]},{"year":null,"claim":"How H2AC20 mechanistically links EGFR signaling output to the Zeb-1/E-cadherin transcriptional program remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No chromatin localization or genomic occupancy data for this isoform","No post-translational modification or interacting-partner characterization","No structural or biochemical distinction from other H2A isoforms established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16777","full_name":"Histone H2A type 2-C","aliases":["H2A-clustered histone 20","Histone H2A-GL101","Histone H2A/q"],"length_aa":129,"mass_kda":14.0,"function":"Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. 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/Q16777/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/H2AC20","classification":"Common Essential","n_dependent_lines":1088,"n_total_lines":1165,"dependency_fraction":0.9339055793991416},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/H2AC20","total_profiled":1310},"omim":[{"mim_id":"602797","title":"HISTONE GENE CLUSTER 2, H2A HISTONE FAMILY, MEMBER C; HIST2H2AC","url":"https://www.omim.org/entry/602797"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":23.9}],"url":"https://www.proteinatlas.org/search/H2AC20"},"hgnc":{"alias_symbol":["H2A/q"],"prev_symbol":["H2A","H2AFQ","HIST2H2AC"]},"alphafold":{"accession":"Q16777","domains":[{"cath_id":"1.10.20.10","chopping":"18-110","consensus_level":"medium","plddt":97.8048,"start":18,"end":110}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16777","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16777-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16777-F1-predicted_aligned_error_v6.png","plddt_mean":91.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H2AC20","jax_strain_url":"https://www.jax.org/strain/search?query=H2AC20"},"sequence":{"accession":"Q16777","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16777.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16777/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16777"}},"corpus_meta":[{"pmid":"11893489","id":"PMC_11893489","title":"Histone H2A 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Reassembly after Mitosis.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32708675","citation_count":21,"is_preprint":false},{"pmid":"36888706","id":"PMC_36888706","title":"The TORC1 activates Rpd3L complex to deacetylate Ino80 and H2A.Z and repress autophagy.","date":"2023","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/36888706","citation_count":20,"is_preprint":false},{"pmid":"30910399","id":"PMC_30910399","title":"USP28 regulates deubiquitination of histone H2A and cell proliferation.","date":"2019","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30910399","citation_count":19,"is_preprint":false},{"pmid":"35365397","id":"PMC_35365397","title":"Spotlight on histone H2A variants: From B to X to Z.","date":"2022","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35365397","citation_count":18,"is_preprint":false},{"pmid":"32547065","id":"PMC_32547065","title":"Vital and Distinct Roles of H2A.Z Isoforms in Hepatocellular Carcinoma.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32547065","citation_count":18,"is_preprint":false},{"pmid":"37536340","id":"PMC_37536340","title":"Structural insight into H4K20 methylation on H2A.Z-nucleosome by SUV420H1.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37536340","citation_count":17,"is_preprint":false},{"pmid":"35503594","id":"PMC_35503594","title":"GAS41 mediates proliferation and GEM chemoresistance via H2A.Z.2 and Notch1 in pancreatic cancer.","date":"2022","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/35503594","citation_count":17,"is_preprint":false},{"pmid":"36709316","id":"PMC_36709316","title":"The H2A.Z and NuRD associated protein HMG20A controls early head and heart developmental transcription programs.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36709316","citation_count":16,"is_preprint":false},{"pmid":"36396651","id":"PMC_36396651","title":"H2A.Z deposition by SWR1C involves multiple ATP-dependent steps.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36396651","citation_count":16,"is_preprint":false},{"pmid":"33609493","id":"PMC_33609493","title":"Effects of H2A.B incorporation on nucleosome structures and dynamics.","date":"2021","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/33609493","citation_count":16,"is_preprint":false},{"pmid":"28883625","id":"PMC_28883625","title":"Redundant Functions for Nap1 and Chz1 in H2A.Z Deposition.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28883625","citation_count":16,"is_preprint":false},{"pmid":"28862252","id":"PMC_28862252","title":"Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq.","date":"2017","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/28862252","citation_count":16,"is_preprint":false},{"pmid":"33362208","id":"PMC_33362208","title":"Biparental contributions of the H2A.B histone variant control embryonic development in mice.","date":"2020","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/33362208","citation_count":16,"is_preprint":false},{"pmid":"32664941","id":"PMC_32664941","title":"Molecular mechanism of histone variant H2A.B on stability and assembly of nucleosome and chromatin structures.","date":"2020","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/32664941","citation_count":16,"is_preprint":false},{"pmid":"33967269","id":"PMC_33967269","title":"Tip60 activates Hoxa9 and Meis1 expression through acetylation of H2A.Z, promoting MLL-AF10 and MLL-ENL acute myeloid leukemia.","date":"2021","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/33967269","citation_count":16,"is_preprint":false},{"pmid":"35474148","id":"PMC_35474148","title":"Contribution of the histone variant H2A.Z to expression of responsive genes in plants.","date":"2022","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35474148","citation_count":15,"is_preprint":false},{"pmid":"24957674","id":"PMC_24957674","title":"Yeast X-chromosome-associated protein 5 (Xap5) functions with H2A.Z to suppress aberrant transcripts.","date":"2014","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/24957674","citation_count":15,"is_preprint":false},{"pmid":"32916283","id":"PMC_32916283","title":"Histone H2A.Z is required for androgen receptor-mediated effects on fear memory.","date":"2020","source":"Neurobiology of learning and memory","url":"https://pubmed.ncbi.nlm.nih.gov/32916283","citation_count":15,"is_preprint":false},{"pmid":"30651935","id":"PMC_30651935","title":"Metformin alters H2A.Z dynamics and regulates androgen dependent prostate cancer progression.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/30651935","citation_count":15,"is_preprint":false},{"pmid":"32085641","id":"PMC_32085641","title":"RNA-Guided Genomic Localization of H2A.L.2 Histone Variant.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32085641","citation_count":14,"is_preprint":false},{"pmid":"35606517","id":"PMC_35606517","title":"Mammalian PERIOD2 regulates H2A.Z incorporation in chromatin to orchestrate circadian negative feedback.","date":"2022","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35606517","citation_count":14,"is_preprint":false},{"pmid":"34330317","id":"PMC_34330317","title":"Histone H2A.X phosphorylation and Caspase-Initiated Chromatin Condensation in late-stage erythropoiesis.","date":"2021","source":"Epigenetics & chromatin","url":"https://pubmed.ncbi.nlm.nih.gov/34330317","citation_count":14,"is_preprint":false},{"pmid":"37450495","id":"PMC_37450495","title":"Mechanism of RanGTP priming H2A-H2B release from Kap114 in an atypical RanGTP•Kap114•H2A-H2B complex.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37450495","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41781,"output_tokens":863,"usd":0.069144,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6855,"output_tokens":1049,"usd":0.03025,"stage2_stop_reason":"end_turn"},"total_usd":0.099394,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the corpus, I need to identify papers specifically about H2AC20 (also known as H2A, H2AFQ, HIST2H2AC) — a canonical histone H2A protein.\n\nAfter careful review, paper [62] is the most directly relevant, describing experiments specifically on the Hist2h2ac protein (H2A type 2-C, encoded by HIST2H2AC). The vast majority of the remaining papers concern H2A variants (H2A.Z, H2A.X, H2A.B, macroH2A), which are distinct from canonical H2A (H2AC20). A few papers (e.g., [14], [33], [69], [80], [100]) describe canonical H2A modifications (ubiquitination, neddylation) that apply to H2A-type histones broadly, including H2AC20, but without specifically identifying this isoform.\n\nPaper [59] and [62] directly address canonical H2A genes including HIST2H2AC. Paper [75] addresses canonical H2A biotinylation. Papers on general H2A ubiquitination/deubiquitination may apply but are not specific to this isoform.\n\nI will extract only findings where experiments were directly performed on H2AC20/Hist2h2ac/HIST2H2AC specifically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"The canonical histone H2A isoform Hist2h2ac (HIST2H2AC/H2AC20) is expressed specifically in undifferentiated/proliferating mammary epithelial cells and is downstream of EGF/EGFR signaling via MEK1/2 and PI3-K pathways. Silencing of Hist2h2ac inhibited EGF-induced Zeb-1 expression and prevented E-cadherin downregulation (epithelial-mesenchymal transition markers), an effect rescued by Hist2h2ac re-expression. Knockdown also blocked EGF-induced proliferation despite increased EGFR/ERBB2/ERK1/2 activation, placing Hist2h2ac downstream of EGFR signaling and as a regulator of oncogenic EMT and proliferation programs.\",\n      \"method\": \"Mass spectrometry screening of histone levels during differentiation; siRNA-mediated silencing; re-expression rescue; qRT-PCR; Western blot; cell proliferation assays in HC11, EpH4, MC4-L2, and T47-D cell lines\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, multiple orthogonal methods (MS identification, siRNA knockdown, rescue, proliferation assay), clean loss-of-function with defined phenotypic readouts and pathway placement downstream of EGFR\",\n      \"pmids\": [\"28288875\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Hist2h2ac (H2AC20/HIST2H2AC), a canonical H2A histone isoform, is expressed in proliferating/undifferentiated mammary epithelial cells downstream of EGFR-MEK/PI3K signaling, where it promotes EGF-induced cell proliferation and epithelial-mesenchymal transition by supporting Zeb-1 expression and E-cadherin downregulation; beyond this, no further mechanistic findings specific to this isoform (as distinct from other H2A variants) are established in the available literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H2AC20 (Hist2h2ac/HIST2H2AC) is a canonical histone H2A isoform whose expression marks undifferentiated, proliferating mammary epithelial cells and operates as a downstream effector of EGF/EGFR signaling acting through the MEK1/2 and PI3-K pathways [#0]. Silencing of Hist2h2ac blocks EGF-induced Zeb-1 expression and prevents E-cadherin downregulation, and re-expression rescues these defects, placing this isoform within the epithelial-mesenchymal transition program; its knockdown also abolishes EGF-induced proliferation despite intact upstream EGFR/ERBB2/ERK1/2 activation, indicating it acts downstream of receptor signaling to drive proliferation and EMT [#0]. Beyond this single characterization in mammary epithelial cells, no further mechanism specific to this H2A isoform has been established in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that a specific canonical H2A isoform, rather than H2A variants generally, is selectively expressed in proliferating mammary epithelial cells and functions as a downstream effector of EGFR signaling driving EMT and proliferation.\",\n      \"evidence\": \"Mass spectrometry of histone levels during differentiation, siRNA silencing with re-expression rescue, and proliferation/EMT marker assays across HC11, EpH4, MC4-L2, and T47-D cell lines\",\n      \"pmids\": [\"28288875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular mechanism by which a canonical histone isoform selectively controls Zeb-1/E-cadherin transcription is defined\",\n        \"Whether the phenotype reflects isoform-specific chromatin incorporation versus a non-canonical function is not resolved\",\n        \"Findings come from a single lab and cultured cell lines without in vivo validation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How H2AC20 mechanistically links EGFR signaling output to the Zeb-1/E-cadherin transcriptional program remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No chromatin localization or genomic occupancy data for this isoform\",\n        \"No post-translational modification or interacting-partner characterization\",\n        \"No structural or biochemical distinction from other H2A isoforms established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}