{"gene":"H2BC15","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2021,"finding":"HIST1H2BN (H2BC15) knockdown in prostate cancer cells (DU145 and PC3) inhibited cell proliferation, migration, and EMT phenotype. Mechanistically, downregulating HIST1H2BN diminished the expression and DNA-binding activity of NF-κB p65, which in turn reduced expression of MMP2 and MMP9, establishing a HIST1H2BN–NF-κB–EMT regulatory axis in oncogenesis.","method":"siRNA knockdown in prostate cancer cell lines, proliferation and migration assays, EMT marker assessment, NF-κB p65 expression and binding activity assays","journal":"Genes & genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single study, cell-line knockdown with pathway readout but no reconstitution, mutagenesis, or structural validation; mechanism is inferred from correlation of NF-κB activity changes with H2BC15 loss","pmids":["34537918"],"is_preprint":false},{"year":2023,"finding":"Approximately 12% of histone H2B molecules in mammalian brain contain a post-translational modification at Asp25, present as the D-enantiomer (D-isoAsp-25) linked to Gly26 via the side-chain carboxyl. This modification is enriched in brain relative to liver, thymus, and HeLa cells, as demonstrated by a highly selective polyclonal antibody.","method":"Polyclonal antibody characterization with specificity validation; tissue fractionation and immunodetection across brain, liver, thymus, and HeLa cells","journal":"Amino acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method (antibody-based detection); modification site identified on histone H2B but not mapped specifically to H2BC15 paralog; no functional consequence demonstrated","pmids":["36717395"],"is_preprint":false}],"current_model":"H2BC15 (HIST1H2BN) is a replication-dependent histone H2B whose transcription is activated at the G1/S cell cycle boundary; in prostate cancer cells, its loss suppresses NF-κB p65 activity and downstream MMP2/MMP9 expression to reduce proliferation and EMT, suggesting a role in oncogenic signaling, though the direct molecular mechanism linking the histone to NF-κB remains uncharacterized."},"narrative":{"mechanistic_narrative":"H2BC15 (HIST1H2BN) is a histone H2B family member implicated in oncogenic signaling in prostate cancer, where its knockdown inhibits cell proliferation, migration, and the EMT phenotype by diminishing the expression and DNA-binding activity of NF-κB p65 and thereby reducing downstream MMP2 and MMP9 expression [PMID:34537918]. The direct molecular mechanism linking the histone to NF-κB activity is not characterized in the available corpus. Separately, histone H2B in mammalian brain carries an Asp25 D-isoAsp modification enriched relative to other tissues, but this modification has not been mapped specifically to the H2BC15 paralog [PMID:36717395]. Beyond these two Low-confidence observations, no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":2021,"claim":"Whether this H2B paralog contributes to cancer phenotypes was unknown; knockdown linked it to an NF-κB–MMP–EMT axis, framing it as a candidate oncogenic regulator.","evidence":"siRNA knockdown in DU145 and PC3 prostate cancer lines with proliferation, migration, EMT marker, and NF-κB p65 binding-activity assays","pmids":["34537918"],"confidence":"Low","gaps":["Mechanism inferred from correlation; no reconstitution, mutagenesis, or rescue establishing direct causality","How a histone protein modulates NF-κB p65 expression and DNA binding is undefined","Single lab, single study, restricted to two cell lines"]},{"year":2023,"claim":"Whether H2B carries tissue-specific covalent modifications was addressed by detecting a brain-enriched Asp25 D-isoAsp modification, raising the possibility of paralog-specific regulation.","evidence":"Polyclonal antibody specificity validation and immunodetection across brain, liver, thymus, and HeLa cells","pmids":["36717395"],"confidence":"Low","gaps":["Antibody-based detection only; not mapped specifically to the H2BC15 paralog","No functional consequence of the modification demonstrated","Single method and single lab"]},{"year":null,"claim":"The direct molecular mechanism by which H2BC15 influences NF-κB signaling, and whether its chromatin/histone function connects to that signaling, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical link between the histone and NF-κB established","No demonstration that H2BC15 deposition or modification drives the cancer phenotype"]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99877","full_name":"Histone H2B type 1-N","aliases":["Histone H2B.d","H2B/d"],"length_aa":126,"mass_kda":13.9,"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/Q99877/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/H2BC15","classification":"Common Essential","n_dependent_lines":1155,"n_total_lines":1165,"dependency_fraction":0.9914163090128756},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/H2BC15","total_profiled":1310},"omim":[{"mim_id":"602801","title":"HISTONE GENE CLUSTER 1, H2B HISTONE FAMILY, MEMBER N; HIST1H2BN","url":"https://www.omim.org/entry/602801"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in some","driving_tissues":[],"url":"https://www.proteinatlas.org/search/H2BC15"},"hgnc":{"alias_symbol":["H2B/d"],"prev_symbol":["H2BFD","HIST1H2BN"]},"alphafold":{"accession":"Q99877","domains":[{"cath_id":"1.10.20.10","chopping":"37-124","consensus_level":"high","plddt":95.7064,"start":37,"end":124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99877","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99877-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99877-F1-predicted_aligned_error_v6.png","plddt_mean":87.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H2BC15","jax_strain_url":"https://www.jax.org/strain/search?query=H2BC15"},"sequence":{"accession":"Q99877","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99877.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99877/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99877"}},"corpus_meta":[{"pmid":"8876167","id":"PMC_8876167","title":"CDP/cut is the DNA-binding subunit of histone gene transcription factor HiNF-D: a mechanism for gene regulation at the G1/S phase cell cycle transition point independent of transcription factor E2F.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8876167","citation_count":115,"is_preprint":false},{"pmid":"4136175","id":"PMC_4136175","title":"Antigen-specific thymus cell factors in the genetic control of the immune response to poly-(tyrosyl, glutamyl)-poly-D, L-alanyl--poly-lysyl.","date":"1974","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/4136175","citation_count":115,"is_preprint":false},{"pmid":"6222135","id":"PMC_6222135","title":"Early development of the T cell repertoire. 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Preferential induction of hyporesponsiveness to the D-end of the major histocompatibility complex in the hapten-specific cytotoxic T cell response.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6195256","citation_count":4,"is_preprint":false},{"pmid":"6641743","id":"PMC_6641743","title":"Rapidly phosphorylated histone-like proteins are modulated in the course of transcription block by 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole.","date":"1983","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/6641743","citation_count":4,"is_preprint":false},{"pmid":"6187857","id":"PMC_6187857","title":"Target determinants for F1 hybrid anti-parental H-2d cell-mediated lympholysis: self antigens controlled by the D end.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6187857","citation_count":4,"is_preprint":false},{"pmid":"27021916","id":"PMC_27021916","title":"Evolution of GC content in the histone gene repeating units from Drosophila lutescens, D. takahashii and D. pseudoobscura.","date":"2016","source":"Genes & genetic systems","url":"https://pubmed.ncbi.nlm.nih.gov/27021916","citation_count":3,"is_preprint":false},{"pmid":"9364425","id":"PMC_9364425","title":"Immunogenic properties of synthetic fragments of Sm-D protein in normal and lupus mice.","date":"1997","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/9364425","citation_count":3,"is_preprint":false},{"pmid":"12355424","id":"PMC_12355424","title":"Differences in antigen processing with haplotype-mismatched MHC class II heterodimers: Aalpha(d)Abeta(b) heterodimers participate in early endosomal processing.","date":"2002","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12355424","citation_count":3,"is_preprint":false},{"pmid":"9022038","id":"PMC_9022038","title":"Lack of F1 anti-parental resistance in H-2b/d F1 hybrids devoid of beta2-microglobulin.","date":"1997","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/9022038","citation_count":3,"is_preprint":false},{"pmid":"34967918","id":"PMC_34967918","title":"MST1 mediates the N-methyl-D-aspartate-induced excitotoxicity in mouse cortical neurons.","date":"2021","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/34967918","citation_count":2,"is_preprint":false},{"pmid":"39198619","id":"PMC_39198619","title":"Genome-wide analysis of the biophysical properties of chromatin and nuclear proteins in living cells with Hi-D.","date":"2024","source":"Nature protocols","url":"https://pubmed.ncbi.nlm.nih.gov/39198619","citation_count":2,"is_preprint":false},{"pmid":"39314463","id":"PMC_39314463","title":"Multifaceted roles of H2B mono-ubiquitylation in D-loop metabolism during homologous recombination repair.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39314463","citation_count":0,"is_preprint":false},{"pmid":"38811654","id":"PMC_38811654","title":"Validation of novel conditional ligands and large-scale detection of antigen-specific T cells for H-2Dd and H-2Kd.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38811654","citation_count":0,"is_preprint":false},{"pmid":"36717395","id":"PMC_36717395","title":"Characterization of a polyclonal antibody that is highly selective for the D-isoAsp-25 variant of mammalian histone H2B.","date":"2023","source":"Amino acids","url":"https://pubmed.ncbi.nlm.nih.gov/36717395","citation_count":0,"is_preprint":false},{"pmid":"6222790","id":"PMC_6222790","title":"Suppressive effects of soluble histocompatibility antigens on the in vitro generation of cytotoxic T cells to D-end alloantigens.","date":"1983","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/6222790","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23049,"output_tokens":1134,"usd":0.043078,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7065,"output_tokens":1103,"usd":0.03145,"stage2_stop_reason":"end_turn"},"total_usd":0.074528,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking at the papers, I need to identify which ones are actually about H2BC15 (also known as H2B/d, H2BFD, HIST1H2BN) - a canonical histone H2B protein-coding gene.\n\nLet me classify each paper:\n- Papers about MHC H-2 haplotypes (H-2b, H-2d, H-2k, etc.): These are about mouse MHC genes, NOT histone H2BC15. These are symbol/context collisions.\n- Papers genuinely about histone H2B biology: Need to evaluate carefully.\n\nRelevant papers:\n- PMID:34537918: Directly about HIST1H2BN (= H2BC15) in prostate cancer, NF-κB pathway\n- PMID:36717395: About histone H2B Asp25 D-isoAsp modification\n- PMID:8876167: HiNF-D complex regulating histone H2B/H4 gene transcription at G1/S\n- PMID:23463099: H2A/H2B eviction in V(D)J recombination\n- PMID:39945322 & 39314463: H2B mono-ubiquitylation in HR repair (yeast ortholog)\n- PMID:34088983: RNF20/RNF40-mediated H2B monoubiquitination\n- PMID:21359316: Histones in mitochondria\n- PMID:31750234: H2A.X/H2B in DNA damage/apoptosis\n- PMID:34967918: MST1 phosphorylation of histone H2B\n\nMost of these are about generic H2B biology, not specifically H2BC15/HIST1H2BN. Only PMID:34537918 directly studies HIST1H2BN specifically.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2021,\n      \"finding\": \"HIST1H2BN (H2BC15) knockdown in prostate cancer cells (DU145 and PC3) inhibited cell proliferation, migration, and EMT phenotype. Mechanistically, downregulating HIST1H2BN diminished the expression and DNA-binding activity of NF-κB p65, which in turn reduced expression of MMP2 and MMP9, establishing a HIST1H2BN–NF-κB–EMT regulatory axis in oncogenesis.\",\n      \"method\": \"siRNA knockdown in prostate cancer cell lines, proliferation and migration assays, EMT marker assessment, NF-κB p65 expression and binding activity assays\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single study, cell-line knockdown with pathway readout but no reconstitution, mutagenesis, or structural validation; mechanism is inferred from correlation of NF-κB activity changes with H2BC15 loss\",\n      \"pmids\": [\"34537918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Approximately 12% of histone H2B molecules in mammalian brain contain a post-translational modification at Asp25, present as the D-enantiomer (D-isoAsp-25) linked to Gly26 via the side-chain carboxyl. This modification is enriched in brain relative to liver, thymus, and HeLa cells, as demonstrated by a highly selective polyclonal antibody.\",\n      \"method\": \"Polyclonal antibody characterization with specificity validation; tissue fractionation and immunodetection across brain, liver, thymus, and HeLa cells\",\n      \"journal\": \"Amino acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method (antibody-based detection); modification site identified on histone H2B but not mapped specifically to H2BC15 paralog; no functional consequence demonstrated\",\n      \"pmids\": [\"36717395\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"H2BC15 (HIST1H2BN) is a replication-dependent histone H2B whose transcription is activated at the G1/S cell cycle boundary; in prostate cancer cells, its loss suppresses NF-κB p65 activity and downstream MMP2/MMP9 expression to reduce proliferation and EMT, suggesting a role in oncogenic signaling, though the direct molecular mechanism linking the histone to NF-κB remains uncharacterized.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H2BC15 (HIST1H2BN) is a histone H2B family member implicated in oncogenic signaling in prostate cancer, where its knockdown inhibits cell proliferation, migration, and the EMT phenotype by diminishing the expression and DNA-binding activity of NF-\\u03baB p65 and thereby reducing downstream MMP2 and MMP9 expression [#0]. The direct molecular mechanism linking the histone to NF-\\u03baB activity is not characterized in the available corpus. Separately, histone H2B in mammalian brain carries an Asp25 D-isoAsp modification enriched relative to other tissues, but this modification has not been mapped specifically to the H2BC15 paralog [#1]. Beyond these two Low-confidence observations, no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether this H2B paralog contributes to cancer phenotypes was unknown; knockdown linked it to an NF-\\u03baB\\u2013MMP\\u2013EMT axis, framing it as a candidate oncogenic regulator.\",\n      \"evidence\": \"siRNA knockdown in DU145 and PC3 prostate cancer lines with proliferation, migration, EMT marker, and NF-\\u03baB p65 binding-activity assays\",\n      \"pmids\": [\"34537918\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Mechanism inferred from correlation; no reconstitution, mutagenesis, or rescue establishing direct causality\",\n        \"How a histone protein modulates NF-\\u03baB p65 expression and DNA binding is undefined\",\n        \"Single lab, single study, restricted to two cell lines\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether H2B carries tissue-specific covalent modifications was addressed by detecting a brain-enriched Asp25 D-isoAsp modification, raising the possibility of paralog-specific regulation.\",\n      \"evidence\": \"Polyclonal antibody specificity validation and immunodetection across brain, liver, thymus, and HeLa cells\",\n      \"pmids\": [\"36717395\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Antibody-based detection only; not mapped specifically to the H2BC15 paralog\",\n        \"No functional consequence of the modification demonstrated\",\n        \"Single method and single lab\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct molecular mechanism by which H2BC15 influences NF-\\u03baB signaling, and whether its chromatin/histone function connects to that signaling, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical link between the histone and NF-\\u03baB established\",\n        \"No demonstration that H2BC15 deposition or modification drives the cancer phenotype\"\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":"win","faith_supported":1,"faith_total":1,"faith_pct":100.0}}