{"gene":"H4C1","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2019,"finding":"H4C1 (HIST1H4A) protein was detected as a lysine-lactylation (Kla) modified protein in diabetic cardiomyopathy heart tissue, with the H4C1-K32 site showing notably elevated lactylation modification in the DCM group compared to controls, placing histone H4 lactylation in pathways related to glucose metabolism and DCM.","method":"Liquid chromatography with tandem mass spectrometry (LC-MS/MS) lactylome-proteome analysis on heart tissues from db/db (DCM) vs. db/m (control) mice; bioinformatics subcellular localization and pathway analysis","journal":"Journal of diabetes research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single proteomics dataset, single lab, no functional validation of the specific H4C1-K32 lactylation site, no writer/eraser/reader identified","pmids":["42029413"],"is_preprint":false},{"year":2024,"finding":"HIST1H4A (H4C1) was identified as a canonical autoantibody target in idiopathic inflammatory myopathy (IIM) patients; autoantibody-associated RNAs including those bound by anti-HIST1H4A antibodies activated TLR7/8 signaling in PBMCs to produce interferon-α and IL-6, linking histone H4 immune complexes to inflammatory signaling.","method":"1581-antigen autoantibody array profiling of IIM patient IgG; TLR7/8 activation assays in healthy donor PBMCs; correlation of HIST1H4A autoreactivity with TLR7/8 activation readouts","journal":"Arthritis & rheumatology (Hoboken, N.J.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single study, indirect mechanism (autoantibody-RNA complex activating TLRs), no direct biochemical reconstitution of H4C1 role","pmids":["39279150"],"is_preprint":false},{"year":2023,"finding":"CRISPR loss-of-function screen identified HIST1H4A (H4C1) as a negative regulator of cancer stemness in triple-negative breast cancer; its deletion enhanced paclitaxel resistance, placing it functionally upstream of stemness maintenance.","method":"Genome-wide CRISPR synthetic lethality screen (in vitro and in vivo orthotopic transplantation models) in TNBC cell lines; loss-of-function deletion with paclitaxel resistance as phenotypic readout","journal":"Oncogenesis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — CRISPR screen identifies phenotypic association but no molecular mechanism or pathway placement for H4C1 specifically; single lab, no mechanistic follow-up on H4C1","pmids":["37932309"],"is_preprint":false},{"year":2025,"finding":"H4C1 protein was elevated in plasma extracellular vesicles from MASLD patients with advanced steatosis (S3) compared to mild steatosis (S1), indicating differential packaging of histone H4 into circulating EVs during hepatic steatosis progression.","method":"Proteomic profiling of plasma-derived EVs by mass spectrometry from 70 MASLD patients; differential expression analysis with MR-based liver imaging correlation","journal":"Biomolecules","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preliminary proteomics study, no mechanistic investigation of H4C1 function in EV packaging or steatosis","pmids":["41301514"],"is_preprint":false}],"current_model":"H4C1 (histone H4) is a core chromatin packaging protein whose expression is linked to cell cycle progression and DNA replication; available experimental evidence from the corpus establishes that its K32 site undergoes lysine lactylation in diabetic cardiomyopathy, that immune complexes containing anti-H4C1 autoantibodies can activate TLR7/8 inflammatory signaling, and that its loss-of-function promotes cancer stemness and paclitaxel resistance in TNBC, but no direct biochemical reconstitution, structural study, or enzymatic mechanism study of H4C1 itself is present in the retrieved literature."},"narrative":{"mechanistic_narrative":"H4C1 encodes a core histone H4 protein involved in chromatin packaging, with the available corpus characterizing it only through disease-associated profiling rather than direct biochemical or structural study. Mass spectrometry of diabetic cardiomyopathy heart tissue identified H4C1 as a target of lysine lactylation, with elevated modification at the K32 site linking histone H4 lactylation to glucose-metabolism-associated chromatin changes [PMID:42029413]. In autoimmune inflammatory myopathy, H4C1 is a canonical autoantibody target, and anti-H4C1 immune complexes carrying associated RNAs activate TLR7/8 signaling in PBMCs to drive interferon-α and IL-6 production [PMID:39279150]. A CRISPR loss-of-function screen placed H4C1 as a negative regulator of cancer stemness in triple-negative breast cancer, where its deletion enhanced paclitaxel resistance [PMID:37932309], and proteomic profiling found H4C1 enriched in circulating plasma extracellular vesicles during advanced hepatic steatosis [PMID:41301514]. No direct enzymatic mechanism, structural model, or biochemical reconstitution of H4C1 itself has been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Whether histone H4 carries metabolically driven post-translational marks in cardiac disease was unknown; lactylome profiling established H4C1 as a lactylation substrate at K32 in diabetic cardiomyopathy.","evidence":"LC-MS/MS lactylome-proteome analysis of db/db versus db/m mouse heart tissue with bioinformatic pathway mapping","pmids":["42029413"],"confidence":"Low","gaps":["No writer, eraser, or reader of H4-K32 lactylation identified","No functional validation that K32 lactylation alters chromatin or transcription","Single proteomics dataset without orthogonal confirmation"]},{"year":2023,"claim":"The functional role of H4C1 in tumor cell plasticity was unknown; a CRISPR screen showed its loss promotes cancer stemness and chemoresistance, placing it as a negative regulator of stemness in TNBC.","evidence":"Genome-wide CRISPR synthetic lethality screen in TNBC cell lines and orthotopic models with paclitaxel resistance readout","pmids":["37932309"],"confidence":"Low","gaps":["No molecular mechanism linking H4C1 loss to stemness","No pathway placement for H4C1 in chemoresistance","Single lab, no mechanistic follow-up"]},{"year":2024,"claim":"Whether histone H4 contributes to inflammatory signaling beyond chromatin was unclear; autoantibody profiling showed anti-H4C1 immune complexes activate TLR7/8 to produce inflammatory cytokines.","evidence":"Autoantibody array profiling of IIM patient IgG plus TLR7/8 activation assays in healthy donor PBMCs","pmids":["39279150"],"confidence":"Low","gaps":["Mechanism is indirect via autoantibody-RNA complexes, not H4C1 itself","No biochemical reconstitution of the immune complex activity","Causal contribution of H4C1 versus bound RNA not separated"]},{"year":2025,"claim":"Whether H4C1 is exported in circulating vesicles during liver disease was unknown; EV proteomics showed elevated H4C1 in plasma EVs with advancing hepatic steatosis.","evidence":"Mass spectrometry proteomics of plasma-derived EVs from 70 MASLD patients with imaging correlation","pmids":["41301514"],"confidence":"Low","gaps":["No mechanism for selective EV packaging of H4C1","Functional role in steatosis progression untested","Single preliminary cohort study"]},{"year":null,"claim":"No direct biochemical, structural, or enzymatic study of H4C1 establishes how its modifications or chromatin function mechanistically drive the disease associations observed.","evidence":"Absent from the available corpus","pmids":[],"confidence":"Low","gaps":["No structural model or reconstitution of H4C1","No identified enzymes acting on H4C1 modification sites","No mechanistic link between chromatin function and the reported phenotypes"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P62805","full_name":"Histone H4","aliases":[],"length_aa":103,"mass_kda":11.4,"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/P62805/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/H4C1","classification":"Not Classified","n_dependent_lines":25,"n_total_lines":1208,"dependency_fraction":0.020695364238410598},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"H2AFZ","stoichiometry":10.0},{"gene":"EPN1","stoichiometry":0.2},{"gene":"H1F0","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2},{"gene":"HIST2H2BE","stoichiometry":0.2},{"gene":"HMGA1","stoichiometry":0.2},{"gene":"HMGN5","stoichiometry":0.2},{"gene":"MAP4K4","stoichiometry":0.2},{"gene":"MCM10","stoichiometry":0.2},{"gene":"MYO1E","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/H4C1","total_profiled":1310},"omim":[{"mim_id":"619456","title":"CDC42 SMALL EFFECTOR 1; CDC42SE1","url":"https://www.omim.org/entry/619456"},{"mim_id":"602822","title":"H4 CLUSTERED HISTONE 1; H4C1","url":"https://www.omim.org/entry/602822"},{"mim_id":"300825","title":"RETINOBLASTOMA-BINDING PROTEIN 7; RBBP7","url":"https://www.omim.org/entry/300825"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":1.6},{"tissue":"lymphoid tissue","ntpm":3.2}],"url":"https://www.proteinatlas.org/search/H4C1"},"hgnc":{"alias_symbol":[],"prev_symbol":["H4FA","HIST1H4A"]},"alphafold":{"accession":"P62805","domains":[{"cath_id":"1.10.20.10","chopping":"27-93","consensus_level":"medium","plddt":97.32,"start":27,"end":93}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P62805","model_url":"https://alphafold.ebi.ac.uk/files/AF-P62805-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P62805-F1-predicted_aligned_error_v6.png","plddt_mean":89.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H4C1","jax_strain_url":"https://www.jax.org/strain/search?query=H4C1"},"sequence":{"accession":"P62805","fasta_url":"https://rest.uniprot.org/uniprotkb/P62805.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P62805/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P62805"}},"corpus_meta":[{"pmid":"24905804","id":"PMC_24905804","title":"High-resolution molecular validation of self-renewal and spontaneous differentiation in clinical-grade adipose-tissue derived human mesenchymal stem cells.","date":"2014","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24905804","citation_count":139,"is_preprint":false},{"pmid":"31701227","id":"PMC_31701227","title":"Proteomics in cerebrospinal fluid and spinal cord suggests UCHL1, MAP2 and GPNMB as biomarkers and underpins importance of transcriptional pathways in amyotrophic lateral sclerosis.","date":"2019","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/31701227","citation_count":95,"is_preprint":false},{"pmid":"30646616","id":"PMC_30646616","title":"Preferential Localization of MUC1 Glycoprotein in Exosomes Secreted by Non-Small Cell Lung Carcinoma Cells.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30646616","citation_count":78,"is_preprint":false},{"pmid":"31201998","id":"PMC_31201998","title":"Transcriptome and Regulatory Network Analyses of CD19-CAR-T Immunotherapy for B-ALL.","date":"2019","source":"Genomics, proteomics & bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/31201998","citation_count":44,"is_preprint":false},{"pmid":"27929073","id":"PMC_27929073","title":"RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27929073","citation_count":41,"is_preprint":false},{"pmid":"26176219","id":"PMC_26176219","title":"Molecular Mechanism of the Cell Death Induced by the Histone Deacetylase Pan Inhibitor LBH589 (Panobinostat) in Wilms Tumor Cells.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26176219","citation_count":21,"is_preprint":false},{"pmid":"31424156","id":"PMC_31424156","title":"Proteomic Analysis of Dpy19l2-Deficient Human Globozoospermia Reveals Multiple Molecular Defects.","date":"2019","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/31424156","citation_count":18,"is_preprint":false},{"pmid":"37932309","id":"PMC_37932309","title":"Combined in vitro/in vivo genome-wide CRISPR screens in triple negative breast cancer identify cancer stemness regulators in paclitaxel resistance.","date":"2023","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37932309","citation_count":13,"is_preprint":false},{"pmid":"39279150","id":"PMC_39279150","title":"TLR7/8 Activation in Immune Cells and Muscle by RNA-Containing Immune Complexes: Role in Inflammation and the Pathogenesis of Myositis.","date":"2024","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/39279150","citation_count":9,"is_preprint":false},{"pmid":"34598060","id":"PMC_34598060","title":"Prioritising breast cancer theranostics: A current medical longing in oncology.","date":"2021","source":"Cancer treatment and research communications","url":"https://pubmed.ncbi.nlm.nih.gov/34598060","citation_count":8,"is_preprint":false},{"pmid":"32196466","id":"PMC_32196466","title":"Network-based computational approach to identify genetic links between cardiomyopathy and its risk factors.","date":"2020","source":"IET systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/32196466","citation_count":7,"is_preprint":false},{"pmid":"29407293","id":"PMC_29407293","title":"Comparison of Rejection-Specific Genes in Peripheral Blood and Allograft Biopsy From Kidney Transplant.","date":"2018","source":"Transplantation proceedings","url":"https://pubmed.ncbi.nlm.nih.gov/29407293","citation_count":7,"is_preprint":false},{"pmid":"38795909","id":"PMC_38795909","title":"Proteomic profile of tissue-derived extracellular vesicles from benign odontogenic lesions.","date":"2024","source":"Journal of stomatology, oral and maxillofacial surgery","url":"https://pubmed.ncbi.nlm.nih.gov/38795909","citation_count":4,"is_preprint":false},{"pmid":"31930537","id":"PMC_31930537","title":"About three-fourths of mouse proteins unexpectedly appear at a low position of SDS-PAGE, often as additional isoforms, questioning whether all protein isoforms have been eliminated in gene-knockout cells or organisms.","date":"2020","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/31930537","citation_count":4,"is_preprint":false},{"pmid":"40453371","id":"PMC_40453371","title":"Harnessing miRNA dynamics in HIV-1-infected macrophages: Unveiling new targeted therapeutics using systems biology.","date":"2025","source":"Computational and structural biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/40453371","citation_count":2,"is_preprint":false},{"pmid":"39874541","id":"PMC_39874541","title":"Boosting Natural Killer Cells' Immunotherapy with Amoxicillin-Loaded Liposomes.","date":"2025","source":"Molecular pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/39874541","citation_count":1,"is_preprint":false},{"pmid":"37854181","id":"PMC_37854181","title":"Combining proteomic markers to construct a logistic regression model for polycystic ovary syndrome.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37854181","citation_count":1,"is_preprint":false},{"pmid":"41301514","id":"PMC_41301514","title":"Plasma Extracellular Vesicles Contain Protein Biomarkers for Capturing Stages of Metabolic Dysfunction-Associated Steatotic Liver Disease: A Preliminary Exploratory Study.","date":"2025","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/41301514","citation_count":0,"is_preprint":false},{"pmid":"42029413","id":"PMC_42029413","title":"Integrative Investigation of Lactylome-Proteome Interplay in Diabetic Cardiomyopathy for Pinpointing Disease Development-Associated Pathways or Proteins.","date":"2026","source":"Journal of diabetes research","url":"https://pubmed.ncbi.nlm.nih.gov/42029413","citation_count":0,"is_preprint":false},{"pmid":"40825323","id":"PMC_40825323","title":"Circulating histone H4 values can relate to disease severity in patients with alcoholic hepatitis and cirrhosis.","date":"2025","source":"Cirugia y cirujanos","url":"https://pubmed.ncbi.nlm.nih.gov/40825323","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":27012,"output_tokens":1227,"usd":0.078914,"retried_sync":true,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7771,"output_tokens":1735,"usd":0.041115,"stage2_stop_reason":"end_turn"},"total_usd":0.120029,"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\": 2019,\n      \"finding\": \"H4C1 (HIST1H4A) protein was detected as a lysine-lactylation (Kla) modified protein in diabetic cardiomyopathy heart tissue, with the H4C1-K32 site showing notably elevated lactylation modification in the DCM group compared to controls, placing histone H4 lactylation in pathways related to glucose metabolism and DCM.\",\n      \"method\": \"Liquid chromatography with tandem mass spectrometry (LC-MS/MS) lactylome-proteome analysis on heart tissues from db/db (DCM) vs. db/m (control) mice; bioinformatics subcellular localization and pathway analysis\",\n      \"journal\": \"Journal of diabetes research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single proteomics dataset, single lab, no functional validation of the specific H4C1-K32 lactylation site, no writer/eraser/reader identified\",\n      \"pmids\": [\"42029413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIST1H4A (H4C1) was identified as a canonical autoantibody target in idiopathic inflammatory myopathy (IIM) patients; autoantibody-associated RNAs including those bound by anti-HIST1H4A antibodies activated TLR7/8 signaling in PBMCs to produce interferon-α and IL-6, linking histone H4 immune complexes to inflammatory signaling.\",\n      \"method\": \"1581-antigen autoantibody array profiling of IIM patient IgG; TLR7/8 activation assays in healthy donor PBMCs; correlation of HIST1H4A autoreactivity with TLR7/8 activation readouts\",\n      \"journal\": \"Arthritis & rheumatology (Hoboken, N.J.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single study, indirect mechanism (autoantibody-RNA complex activating TLRs), no direct biochemical reconstitution of H4C1 role\",\n      \"pmids\": [\"39279150\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR loss-of-function screen identified HIST1H4A (H4C1) as a negative regulator of cancer stemness in triple-negative breast cancer; its deletion enhanced paclitaxel resistance, placing it functionally upstream of stemness maintenance.\",\n      \"method\": \"Genome-wide CRISPR synthetic lethality screen (in vitro and in vivo orthotopic transplantation models) in TNBC cell lines; loss-of-function deletion with paclitaxel resistance as phenotypic readout\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — CRISPR screen identifies phenotypic association but no molecular mechanism or pathway placement for H4C1 specifically; single lab, no mechanistic follow-up on H4C1\",\n      \"pmids\": [\"37932309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"H4C1 protein was elevated in plasma extracellular vesicles from MASLD patients with advanced steatosis (S3) compared to mild steatosis (S1), indicating differential packaging of histone H4 into circulating EVs during hepatic steatosis progression.\",\n      \"method\": \"Proteomic profiling of plasma-derived EVs by mass spectrometry from 70 MASLD patients; differential expression analysis with MR-based liver imaging correlation\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preliminary proteomics study, no mechanistic investigation of H4C1 function in EV packaging or steatosis\",\n      \"pmids\": [\"41301514\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"H4C1 (histone H4) is a core chromatin packaging protein whose expression is linked to cell cycle progression and DNA replication; available experimental evidence from the corpus establishes that its K32 site undergoes lysine lactylation in diabetic cardiomyopathy, that immune complexes containing anti-H4C1 autoantibodies can activate TLR7/8 inflammatory signaling, and that its loss-of-function promotes cancer stemness and paclitaxel resistance in TNBC, but no direct biochemical reconstitution, structural study, or enzymatic mechanism study of H4C1 itself is present in the retrieved literature.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H4C1 encodes a core histone H4 protein involved in chromatin packaging, with the available corpus characterizing it only through disease-associated profiling rather than direct biochemical or structural study. Mass spectrometry of diabetic cardiomyopathy heart tissue identified H4C1 as a target of lysine lactylation, with elevated modification at the K32 site linking histone H4 lactylation to glucose-metabolism-associated chromatin changes [#0]. In autoimmune inflammatory myopathy, H4C1 is a canonical autoantibody target, and anti-H4C1 immune complexes carrying associated RNAs activate TLR7/8 signaling in PBMCs to drive interferon-α and IL-6 production [#1]. A CRISPR loss-of-function screen placed H4C1 as a negative regulator of cancer stemness in triple-negative breast cancer, where its deletion enhanced paclitaxel resistance [#2], and proteomic profiling found H4C1 enriched in circulating plasma extracellular vesicles during advanced hepatic steatosis [#3]. No direct enzymatic mechanism, structural model, or biochemical reconstitution of H4C1 itself has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether histone H4 carries metabolically driven post-translational marks in cardiac disease was unknown; lactylome profiling established H4C1 as a lactylation substrate at K32 in diabetic cardiomyopathy.\",\n      \"evidence\": \"LC-MS/MS lactylome-proteome analysis of db/db versus db/m mouse heart tissue with bioinformatic pathway mapping\",\n      \"pmids\": [\"42029413\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No writer, eraser, or reader of H4-K32 lactylation identified\",\n        \"No functional validation that K32 lactylation alters chromatin or transcription\",\n        \"Single proteomics dataset without orthogonal confirmation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The functional role of H4C1 in tumor cell plasticity was unknown; a CRISPR screen showed its loss promotes cancer stemness and chemoresistance, placing it as a negative regulator of stemness in TNBC.\",\n      \"evidence\": \"Genome-wide CRISPR synthetic lethality screen in TNBC cell lines and orthotopic models with paclitaxel resistance readout\",\n      \"pmids\": [\"37932309\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No molecular mechanism linking H4C1 loss to stemness\",\n        \"No pathway placement for H4C1 in chemoresistance\",\n        \"Single lab, no mechanistic follow-up\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether histone H4 contributes to inflammatory signaling beyond chromatin was unclear; autoantibody profiling showed anti-H4C1 immune complexes activate TLR7/8 to produce inflammatory cytokines.\",\n      \"evidence\": \"Autoantibody array profiling of IIM patient IgG plus TLR7/8 activation assays in healthy donor PBMCs\",\n      \"pmids\": [\"39279150\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanism is indirect via autoantibody-RNA complexes, not H4C1 itself\",\n        \"No biochemical reconstitution of the immune complex activity\",\n        \"Causal contribution of H4C1 versus bound RNA not separated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether H4C1 is exported in circulating vesicles during liver disease was unknown; EV proteomics showed elevated H4C1 in plasma EVs with advancing hepatic steatosis.\",\n      \"evidence\": \"Mass spectrometry proteomics of plasma-derived EVs from 70 MASLD patients with imaging correlation\",\n      \"pmids\": [\"41301514\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No mechanism for selective EV packaging of H4C1\",\n        \"Functional role in steatosis progression untested\",\n        \"Single preliminary cohort study\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No direct biochemical, structural, or enzymatic study of H4C1 establishes how its modifications or chromatin function mechanistically drive the disease associations observed.\",\n      \"evidence\": \"Absent from the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model or reconstitution of H4C1\",\n        \"No identified enzymes acting on H4C1 modification sites\",\n        \"No mechanistic link between chromatin function and the reported phenotypes\"\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":"loss","faith_supported":3,"faith_total":3,"faith_pct":100.0}}