{"gene":"H2AC6","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2013,"finding":"Reduced expression of HIST1H2AC (H2AC6) by siRNA knockdown leads to increased rates of cell proliferation and tumorigenicity in bladder cancer cells, indicating a functional role in suppressing cell proliferation distinct from other H2A isoforms. Additionally, discrete elements in the 5' untranslated region of the HIST1H2AC locus confer translational repression, demonstrating isoform-specific post-transcriptional regulation.","method":"siRNA knockdown with cell proliferation and tumorigenicity assays; 5' UTR reporter/translational repression analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean siRNA KD with defined cellular phenotype and 5'UTR functional element identification, single lab, two orthogonal methods","pmids":["23956221"],"is_preprint":false},{"year":2009,"finding":"LC-MS proteomic profiling of primary chronic lymphocytic leukemia (CLL) cells revealed a significant decrease in the relative abundance of histone H2A isoform H2AFL (H2AC6) compared to normal B cells, establishing differential isoform abundance as a feature of CLL chromatin.","method":"LC-MS protein profiling with quantitative comparison across 40 CLL patients and 4 normal individuals; shotgun proteomics for identity confirmation","journal":"Proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative MS with large sample cohort and method validation, single lab","pmids":["19253275"],"is_preprint":false},{"year":2013,"finding":"Polyadenylated transcripts from the HIST1H2AC (H2AC6) locus are produced and their fraction increases during differentiation of human mesenchymal stem cells and human fetal osteoblasts, and following ionizing radiation. These polyadenylated transcripts are transported to the cytoplasm and found on polyribosomes, indicating regulated alternative 3' end processing under specific cellular conditions.","method":"qRT-PCR detection of polyadenylated vs. stem-loop transcripts; polyribosome fractionation; cell differentiation and ionizing radiation models","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — polyribosome fractionation plus qRT-PCR, single lab, two orthogonal methods","pmids":["23717473"],"is_preprint":false},{"year":2022,"finding":"CRISPR activation of HIST1H2AC (H2AC6) in THP-1 cells with NRAS turned off increased cell-proliferative activity, and HIST1H2AC expression was upregulated downstream of NRAS and decreased by MEK inhibitors. Knockdown of HIST1H2AC reduced proliferation in THP-1 cells, placing H2AC6 in the NRAS-MEK downstream proliferative signaling pathway.","method":"CRISPR activation screening; doxycycline-inducible NRAS expression system; MEK inhibitor treatment; siRNA knockdown with proliferation assay","journal":"Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR activation plus knockdown phenotype plus epistasis with MEK inhibitor, single lab, multiple orthogonal methods","pmids":["36358254"],"is_preprint":false}],"current_model":"H2AC6 (HIST1H2AC/H2AFL) is a replication-dependent histone H2A isoform whose expression level is functionally non-redundant: siRNA knockdown increases cell proliferation and tumorigenicity, while its overactivation via CRISPR places it downstream of the NRAS-MEK signaling axis to promote proliferation; its abundance is reduced in CLL chromatin relative to normal B cells, its locus contains 5' UTR elements conferring translational repression, and its transcripts undergo regulated alternative polyadenylation during differentiation and after DNA damage, with polyadenylated forms exported to the cytoplasm and loaded onto polyribosomes."},"narrative":{"mechanistic_narrative":"H2AC6 (HIST1H2AC/H2AFL) is a replication-dependent histone H2A isoform whose expression level exerts isoform-specific, non-redundant control over cell proliferation [PMID:23956221, PMID:36358254]. Its abundance is functionally consequential rather than interchangeable with other H2A variants: siRNA knockdown in bladder cancer cells increases proliferation and tumorigenicity, identifying a proliferation-restraining role [PMID:23956221], while its reduced relative abundance in chronic lymphocytic leukemia chromatin marks differential isoform usage in malignancy [PMID:19253275]. In a distinct cellular context, CRISPR activation in THP-1 cells increases proliferation and places H2AC6 expression downstream of the NRAS-MEK signaling axis, with knockdown reducing proliferation and MEK inhibition lowering its expression [PMID:36358254]. H2AC6 is subject to layered isoform-specific post-transcriptional regulation: discrete 5' UTR elements confer translational repression [PMID:23956221], and the locus undergoes regulated alternative polyadenylation during differentiation and after ionizing radiation, with polyadenylated transcripts exported to the cytoplasm and loaded onto polyribosomes [PMID:23717473]. The molecular basis by which H2AC6 incorporation into chromatin produces these proliferative outcomes has not been characterized in the available corpus.","teleology":[{"year":2009,"claim":"Established that a specific H2A isoform's abundance, not just bulk histone content, is altered in a malignancy, raising the question of isoform-specific function.","evidence":"Quantitative LC-MS proteomic profiling of primary CLL cells versus normal B cells across a 40-patient cohort","pmids":["19253275"],"confidence":"Medium","gaps":["Does not establish whether reduced H2AC6 abundance is causal or consequential in CLL","No mechanism linking isoform abundance to chromatin state or transcription"]},{"year":2013,"claim":"Showed that H2AC6 abundance is functionally non-redundant by demonstrating that lowering it accelerates proliferation, and identified a post-transcriptional control point in its 5' UTR.","evidence":"siRNA knockdown with proliferation/tumorigenicity assays plus 5' UTR translational reporter analysis in bladder cancer cells","pmids":["23956221"],"confidence":"Medium","gaps":["Mechanism by which the isoform restrains proliferation is unknown","5' UTR trans-acting factors not identified","Single cancer-cell context"]},{"year":2013,"claim":"Revealed that the H2AC6 locus is regulated by alternative 3' end processing tied to differentiation and DNA damage, with polyadenylated transcripts entering cytoplasmic translation.","evidence":"qRT-PCR for polyadenylated vs. stem-loop transcripts and polyribosome fractionation in differentiating mesenchymal/osteoblast models and after ionizing radiation","pmids":["23717473"],"confidence":"Medium","gaps":["Functional consequence of the polyadenylated isoform versus the stem-loop form is unresolved","Polyadenylation machinery and signals not defined"]},{"year":2022,"claim":"Positioned H2AC6 expression within an oncogenic signaling pathway, showing its proliferative output is wired downstream of NRAS-MEK.","evidence":"CRISPR activation screening, doxycycline-inducible NRAS, MEK inhibitor epistasis, and siRNA knockdown with proliferation assays in THP-1 cells","pmids":["36358254"],"confidence":"Medium","gaps":["Direction of the proliferative effect (activation increases proliferation here vs. knockdown increasing it in bladder cells) is context-dependent and unreconciled","No direct transcriptional link from MEK to the H2AC6 promoter shown"]},{"year":null,"claim":"How H2AC6 incorporation into nucleosomes mechanistically alters chromatin to control proliferation, and why its directional effect differs across cell types, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural or chromatin-incorporation mechanism characterized","No identified chromatin readers or modifying enzymes specific to this isoform","Context-dependence between tumor types unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q93077","full_name":"Histone H2A type 1-C","aliases":["H2A-clustered histone 6","Histone H2A/l"],"length_aa":130,"mass_kda":14.1,"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/Q93077/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/H2AC6","classification":"Common Essential","n_dependent_lines":592,"n_total_lines":1208,"dependency_fraction":0.4900662251655629},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUCKS1","stoichiometry":10.0},{"gene":"NUMA1","stoichiometry":10.0},{"gene":"H2AFZ","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/H2AC6","total_profiled":1310},"omim":[{"mim_id":"602794","title":"HISTONE GENE CLUSTER 1, H2A HISTONE FAMILY, MEMBER C; HIST1H2AC","url":"https://www.omim.org/entry/602794"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/H2AC6"},"hgnc":{"alias_symbol":[],"prev_symbol":["H2AFL","HIST1H2AC"]},"alphafold":{"accession":"Q93077","domains":[{"cath_id":"1.10.20.10","chopping":"19-109","consensus_level":"medium","plddt":97.8579,"start":19,"end":109}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q93077","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q93077-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q93077-F1-predicted_aligned_error_v6.png","plddt_mean":91.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H2AC6","jax_strain_url":"https://www.jax.org/strain/search?query=H2AC6"},"sequence":{"accession":"Q93077","fasta_url":"https://rest.uniprot.org/uniprotkb/Q93077.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q93077/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q93077"}},"corpus_meta":[{"pmid":"23717473","id":"PMC_23717473","title":"A subset of histone H2B genes produces polyadenylated mRNAs under a variety of cellular conditions.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23717473","citation_count":43,"is_preprint":false},{"pmid":"28178938","id":"PMC_28178938","title":"Messenger RNA and MicroRNA transcriptomic signatures of cardiometabolic risk factors.","date":"2017","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28178938","citation_count":32,"is_preprint":false},{"pmid":"23956221","id":"PMC_23956221","title":"Increasing the complexity of chromatin: functionally distinct roles for replication-dependent histone H2A isoforms in cell proliferation and carcinogenesis.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23956221","citation_count":23,"is_preprint":false},{"pmid":"17977650","id":"PMC_17977650","title":"Identification of differentially expressed genes after PPM1D silencing in breast cancer.","date":"2007","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/17977650","citation_count":21,"is_preprint":false},{"pmid":"19253275","id":"PMC_19253275","title":"Validation of an LC-MS based approach for profiling histones in chronic lymphocytic leukemia.","date":"2009","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/19253275","citation_count":20,"is_preprint":false},{"pmid":"31097152","id":"PMC_31097152","title":"Associations between single nucleotide polymorphisms and erythrocyte parameters in humans: A systematic literature review.","date":"2019","source":"Mutation research. Reviews in mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/31097152","citation_count":13,"is_preprint":false},{"pmid":"36714547","id":"PMC_36714547","title":"High-throughput proteomic characterization of seminal plasma from bulls with contrasting semen quality.","date":"2023","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/36714547","citation_count":8,"is_preprint":false},{"pmid":"23002402","id":"PMC_23002402","title":"Transcriptional and secretomic profiling of epidermal cells exposed to alpha particle radiation.","date":"2012","source":"The open biochemistry journal","url":"https://pubmed.ncbi.nlm.nih.gov/23002402","citation_count":7,"is_preprint":false},{"pmid":"34926670","id":"PMC_34926670","title":"Tribulus terrestris L. protects glomerular endothelial cells via the miR155-H2AC6 interaction network in hypertensive renal injury.","date":"2021","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34926670","citation_count":6,"is_preprint":false},{"pmid":"40463856","id":"PMC_40463856","title":"Unveiling the Therapeutic Potential of Baicalin in Intervertebral Disc Degeneration: Integrative Bulk and Single-Cell Transcriptome Analysis with Experimental Validation of PANoptosis Inhibition.","date":"2025","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/40463856","citation_count":6,"is_preprint":false},{"pmid":"34565095","id":"PMC_34565095","title":"Abnormal expression of TGFBR2, EGF, LRP10, and IQGAP1 is involved in the pathogenesis of coronary artery disease.","date":"2021","source":"Reviews in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34565095","citation_count":5,"is_preprint":false},{"pmid":"38067326","id":"PMC_38067326","title":"Characteristics of ABCC4 and ABCG2 High Expression Subpopulations in CRC-A New Opportunity to Predict Therapy Response.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/38067326","citation_count":4,"is_preprint":false},{"pmid":"40988222","id":"PMC_40988222","title":"Inhibition of lactylation by LRP1 expression increases the risk of intervertebral disc degeneration: A multi-omics summary-based Mendelian randomization analysis.","date":"2025","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40988222","citation_count":3,"is_preprint":false},{"pmid":"36358254","id":"PMC_36358254","title":"Identification of NRAS Downstream Genes with CRISPR Activation Screening.","date":"2022","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/36358254","citation_count":0,"is_preprint":false},{"pmid":"39430218","id":"PMC_39430218","title":"Identifying signature genes and their associations with immune cell infiltration in spinal cord injury.","date":"2024","source":"IBRO neuroscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/39430218","citation_count":0,"is_preprint":false},{"pmid":"40632661","id":"PMC_40632661","title":"Genome-Wide CRISPR-Cas9 Knockout Screening Identifies Genes Modulating Cisplatin-Induced Cytotoxicity in Renal Proximal Tubule Epithelial Cells.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40632661","citation_count":0,"is_preprint":false},{"pmid":"41588020","id":"PMC_41588020","title":"Serum extracellular vesicle RNA profiles in long COVID: insights from exercise-induced gene modulation.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41588020","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11636,"output_tokens":1125,"usd":0.025892,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7730,"output_tokens":1805,"usd":0.041888,"stage2_stop_reason":"end_turn"},"total_usd":0.06778,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Reduced expression of HIST1H2AC (H2AC6) by siRNA knockdown leads to increased rates of cell proliferation and tumorigenicity in bladder cancer cells, indicating a functional role in suppressing cell proliferation distinct from other H2A isoforms. Additionally, discrete elements in the 5' untranslated region of the HIST1H2AC locus confer translational repression, demonstrating isoform-specific post-transcriptional regulation.\",\n      \"method\": \"siRNA knockdown with cell proliferation and tumorigenicity assays; 5' UTR reporter/translational repression analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA KD with defined cellular phenotype and 5'UTR functional element identification, single lab, two orthogonal methods\",\n      \"pmids\": [\"23956221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LC-MS proteomic profiling of primary chronic lymphocytic leukemia (CLL) cells revealed a significant decrease in the relative abundance of histone H2A isoform H2AFL (H2AC6) compared to normal B cells, establishing differential isoform abundance as a feature of CLL chromatin.\",\n      \"method\": \"LC-MS protein profiling with quantitative comparison across 40 CLL patients and 4 normal individuals; shotgun proteomics for identity confirmation\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative MS with large sample cohort and method validation, single lab\",\n      \"pmids\": [\"19253275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Polyadenylated transcripts from the HIST1H2AC (H2AC6) locus are produced and their fraction increases during differentiation of human mesenchymal stem cells and human fetal osteoblasts, and following ionizing radiation. These polyadenylated transcripts are transported to the cytoplasm and found on polyribosomes, indicating regulated alternative 3' end processing under specific cellular conditions.\",\n      \"method\": \"qRT-PCR detection of polyadenylated vs. stem-loop transcripts; polyribosome fractionation; cell differentiation and ionizing radiation models\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — polyribosome fractionation plus qRT-PCR, single lab, two orthogonal methods\",\n      \"pmids\": [\"23717473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR activation of HIST1H2AC (H2AC6) in THP-1 cells with NRAS turned off increased cell-proliferative activity, and HIST1H2AC expression was upregulated downstream of NRAS and decreased by MEK inhibitors. Knockdown of HIST1H2AC reduced proliferation in THP-1 cells, placing H2AC6 in the NRAS-MEK downstream proliferative signaling pathway.\",\n      \"method\": \"CRISPR activation screening; doxycycline-inducible NRAS expression system; MEK inhibitor treatment; siRNA knockdown with proliferation assay\",\n      \"journal\": \"Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR activation plus knockdown phenotype plus epistasis with MEK inhibitor, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"36358254\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"H2AC6 (HIST1H2AC/H2AFL) is a replication-dependent histone H2A isoform whose expression level is functionally non-redundant: siRNA knockdown increases cell proliferation and tumorigenicity, while its overactivation via CRISPR places it downstream of the NRAS-MEK signaling axis to promote proliferation; its abundance is reduced in CLL chromatin relative to normal B cells, its locus contains 5' UTR elements conferring translational repression, and its transcripts undergo regulated alternative polyadenylation during differentiation and after DNA damage, with polyadenylated forms exported to the cytoplasm and loaded onto polyribosomes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H2AC6 (HIST1H2AC/H2AFL) is a replication-dependent histone H2A isoform whose expression level exerts isoform-specific, non-redundant control over cell proliferation [#0, #3]. Its abundance is functionally consequential rather than interchangeable with other H2A variants: siRNA knockdown in bladder cancer cells increases proliferation and tumorigenicity, identifying a proliferation-restraining role [#0], while its reduced relative abundance in chronic lymphocytic leukemia chromatin marks differential isoform usage in malignancy [#1]. In a distinct cellular context, CRISPR activation in THP-1 cells increases proliferation and places H2AC6 expression downstream of the NRAS-MEK signaling axis, with knockdown reducing proliferation and MEK inhibition lowering its expression [#3]. H2AC6 is subject to layered isoform-specific post-transcriptional regulation: discrete 5' UTR elements confer translational repression [#0], and the locus undergoes regulated alternative polyadenylation during differentiation and after ionizing radiation, with polyadenylated transcripts exported to the cytoplasm and loaded onto polyribosomes [#2]. The molecular basis by which H2AC6 incorporation into chromatin produces these proliferative outcomes has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Established that a specific H2A isoform's abundance, not just bulk histone content, is altered in a malignancy, raising the question of isoform-specific function.\",\n      \"evidence\": \"Quantitative LC-MS proteomic profiling of primary CLL cells versus normal B cells across a 40-patient cohort\",\n      \"pmids\": [\"19253275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether reduced H2AC6 abundance is causal or consequential in CLL\", \"No mechanism linking isoform abundance to chromatin state or transcription\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that H2AC6 abundance is functionally non-redundant by demonstrating that lowering it accelerates proliferation, and identified a post-transcriptional control point in its 5' UTR.\",\n      \"evidence\": \"siRNA knockdown with proliferation/tumorigenicity assays plus 5' UTR translational reporter analysis in bladder cancer cells\",\n      \"pmids\": [\"23956221\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which the isoform restrains proliferation is unknown\", \"5' UTR trans-acting factors not identified\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed that the H2AC6 locus is regulated by alternative 3' end processing tied to differentiation and DNA damage, with polyadenylated transcripts entering cytoplasmic translation.\",\n      \"evidence\": \"qRT-PCR for polyadenylated vs. stem-loop transcripts and polyribosome fractionation in differentiating mesenchymal/osteoblast models and after ionizing radiation\",\n      \"pmids\": [\"23717473\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the polyadenylated isoform versus the stem-loop form is unresolved\", \"Polyadenylation machinery and signals not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned H2AC6 expression within an oncogenic signaling pathway, showing its proliferative output is wired downstream of NRAS-MEK.\",\n      \"evidence\": \"CRISPR activation screening, doxycycline-inducible NRAS, MEK inhibitor epistasis, and siRNA knockdown with proliferation assays in THP-1 cells\",\n      \"pmids\": [\"36358254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of the proliferative effect (activation increases proliferation here vs. knockdown increasing it in bladder cells) is context-dependent and unreconciled\", \"No direct transcriptional link from MEK to the H2AC6 promoter shown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How H2AC6 incorporation into nucleosomes mechanistically alters chromatin to control proliferation, and why its directional effect differs across cell types, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or chromatin-incorporation mechanism characterized\", \"No identified chromatin readers or modifying enzymes specific to this isoform\", \"Context-dependence between tumor types unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}