{"gene":"H2BC21","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2012,"finding":"H2BE (Hist2h2be/H2BC21) is a replication-independent histone H2B variant expressed exclusively in olfactory chemosensory neurons. Its expression is reduced by sensory activity and it promotes neuronal cell death; gain- and loss-of-function experiments show that changes in H2be expression affect olfactory function and OR representation. Post-translational modifications of H2BE differ from those of canonical H2B, consistent with a role in altering transcription.","method":"Gain- and loss-of-function mouse genetics, immunostaining, post-translational modification profiling, olfactory function assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with specific phenotypic readouts, PTM profiling, replicated across multiple assays in a single focused study on this specific variant","pmids":["23240083"],"is_preprint":false},{"year":1992,"finding":"The H2B-GL105 gene (an alias for H2BC21/H2BFQ) encodes both a 500 nt cell-cycle-dependent mRNA and a 2300 nt constitutively expressed polyadenylated mRNA via alternative 3' end processing. The gene is located at chromosome 1q21-1q23 and is paired with a functional H2A gene; the cell-cycle-regulated mRNA terminates after the histone dyad symmetry element while the constitutive mRNA extends 1798 nt further and is polyadenylated.","method":"cDNA cloning, Northern blotting, chromosomal in situ hybridization, somatic cell hybrid analysis, cell cycle synchronization","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and sequencing with cell-cycle analysis and chromosomal localization; single lab but multiple orthogonal methods","pmids":["1469070"],"is_preprint":false},{"year":2015,"finding":"HIST1H2BE (H2BC21) is hypomethylated and overexpressed in estrogen deprivation-resistant breast cancer cell lines (C4-12 and LTED) compared with parental MCF-7 cells. Both overexpression and knockdown of HIST1H2BE caused decreased proliferation in breast cancer cell lines, indicating that tightly controlled expression of this histone variant is required for normal cell proliferation.","method":"DNA methylation analysis, qRT-PCR, overexpression and siRNA knockdown with proliferation assays, NanoString histone variant expression panel","journal":"Hormones & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function and gain-of-function with a defined cellular phenotype (proliferation), two orthogonal perturbation approaches, single lab","pmids":["26113056"],"is_preprint":false}],"current_model":"H2BC21 (also known as H2BE/H2BFQ/HIST2H2BE/H2B-GL105) is a histone H2B variant whose best-characterized isoform, expressed exclusively in olfactory neurons, is a replication-independent variant (H2BE) whose levels are regulated by sensory activity to control neuronal lifespan and olfactory receptor representation; the gene also produces alternative mRNAs by differential 3' end processing (cell-cycle-regulated vs. constitutive polyadenylated forms), and its expression must be tightly controlled for normal breast cancer cell proliferation."},"narrative":{"mechanistic_narrative":"H2BC21 encodes a histone H2B variant whose best-characterized form, H2BE, is a replication-independent variant expressed exclusively in olfactory chemosensory neurons, where it links sensory activity to neuronal turnover [PMID:23240083]. Sensory activity reduces H2BE expression, and the variant promotes neuronal cell death; reciprocal gain- and loss-of-function manipulations alter olfactory function and olfactory receptor representation, and H2BE carries post-translational modifications distinct from canonical H2B consistent with a role in modulating transcription [PMID:23240083]. The gene generates two transcript classes by alternative 3' end processing: a short cell-cycle-dependent mRNA terminating after the histone dyad symmetry element and a longer constitutively expressed polyadenylated mRNA [PMID:1469070]. Tightly controlled expression of this variant is also required for normal proliferation, as both overexpression and knockdown reduce breast cancer cell proliferation, and the gene is hypomethylated and overexpressed in estrogen deprivation-resistant lines [PMID:26113056].","teleology":[{"year":1992,"claim":"Established that the gene produces transcripts of two distinct architectures, defining it as both a cell-cycle-regulated and a constitutively expressed histone gene rather than a single replication-coupled histone.","evidence":"cDNA cloning, Northern blotting, chromosomal in situ hybridization, and cell-cycle synchronization mapping the gene to 1q21-1q23 paired with a functional H2A gene","pmids":["1469070"],"confidence":"Medium","gaps":["Functional consequence of the two transcript forms not tested","No protein-level characterization of the encoded variant","Single lab"]},{"year":2012,"claim":"Defined H2BE as a replication-independent H2B variant restricted to olfactory neurons that couples sensory activity to neuronal lifespan and olfactory receptor representation, giving the variant a specific neurobiological function.","evidence":"Reciprocal gain- and loss-of-function mouse genetics with immunostaining, PTM profiling, and olfactory function assays","pmids":["23240083"],"confidence":"High","gaps":["Specific PTMs and their transcriptional targets not molecularly defined","Mechanism linking activity to H2BE downregulation unknown","Function outside olfactory neurons not addressed"]},{"year":2015,"claim":"Showed that dosage of the variant is constrained for cell proliferation and that it is epigenetically deregulated in therapy-resistant breast cancer, extending its relevance beyond neurons.","evidence":"DNA methylation analysis, qRT-PCR, and reciprocal overexpression/siRNA knockdown with proliferation assays in breast cancer cell lines","pmids":["26113056"],"confidence":"Medium","gaps":["Molecular mechanism by which the variant constrains proliferation not defined","Chromatin incorporation in cancer cells not shown","Single lab, cell-line only"]},{"year":null,"claim":"How H2BE incorporation alters chromatin structure and transcription at the molecular level, and how its distinct PTMs are read, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical model of H2BE nucleosomes","Effector proteins recognizing its PTMs not identified","Mechanism connecting variant dosage to cell death and proliferation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0]}],"complexes":["nucleosome"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16778","full_name":"Histone H2B type 2-E","aliases":["H2B-clustered histone 21","Histone H2B-GL105","Histone H2B.q","H2B/q"],"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 Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid","subcellular_location":"Nucleus; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q16778/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/H2BC21","classification":"Common 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HIST2H2BE","url":"https://www.omim.org/entry/601831"}],"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 all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/H2BC21"},"hgnc":{"alias_symbol":["H2B/q","H2B.1","H2BE","H2B-GL105"],"prev_symbol":["H2B","H2BFQ","HIST2H2BE"]},"alphafold":{"accession":"Q16778","domains":[{"cath_id":"1.10.20.10","chopping":"37-124","consensus_level":"high","plddt":95.6343,"start":37,"end":124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16778","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16778-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16778-F1-predicted_aligned_error_v6.png","plddt_mean":88.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=H2BC21","jax_strain_url":"https://www.jax.org/strain/search?query=H2BC21"},"sequence":{"accession":"Q16778","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16778.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16778/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16778"}},"corpus_meta":[{"pmid":"12077605","id":"PMC_12077605","title":"Ubiquitination 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Gene regulatory mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/38331024","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45239,"output_tokens":962,"usd":0.075074,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7463,"output_tokens":1567,"usd":0.038245,"stage2_stop_reason":"end_turn"},"total_usd":0.113319,"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\": 2012,\n      \"finding\": \"H2BE (Hist2h2be/H2BC21) is a replication-independent histone H2B variant expressed exclusively in olfactory chemosensory neurons. Its expression is reduced by sensory activity and it promotes neuronal cell death; gain- and loss-of-function experiments show that changes in H2be expression affect olfactory function and OR representation. Post-translational modifications of H2BE differ from those of canonical H2B, consistent with a role in altering transcription.\",\n      \"method\": \"Gain- and loss-of-function mouse genetics, immunostaining, post-translational modification profiling, olfactory function assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function experiments with specific phenotypic readouts, PTM profiling, replicated across multiple assays in a single focused study on this specific variant\",\n      \"pmids\": [\"23240083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The H2B-GL105 gene (an alias for H2BC21/H2BFQ) encodes both a 500 nt cell-cycle-dependent mRNA and a 2300 nt constitutively expressed polyadenylated mRNA via alternative 3' end processing. The gene is located at chromosome 1q21-1q23 and is paired with a functional H2A gene; the cell-cycle-regulated mRNA terminates after the histone dyad symmetry element while the constitutive mRNA extends 1798 nt further and is polyadenylated.\",\n      \"method\": \"cDNA cloning, Northern blotting, chromosomal in situ hybridization, somatic cell hybrid analysis, cell cycle synchronization\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and sequencing with cell-cycle analysis and chromosomal localization; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"1469070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HIST1H2BE (H2BC21) is hypomethylated and overexpressed in estrogen deprivation-resistant breast cancer cell lines (C4-12 and LTED) compared with parental MCF-7 cells. Both overexpression and knockdown of HIST1H2BE caused decreased proliferation in breast cancer cell lines, indicating that tightly controlled expression of this histone variant is required for normal cell proliferation.\",\n      \"method\": \"DNA methylation analysis, qRT-PCR, overexpression and siRNA knockdown with proliferation assays, NanoString histone variant expression panel\",\n      \"journal\": \"Hormones & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function and gain-of-function with a defined cellular phenotype (proliferation), two orthogonal perturbation approaches, single lab\",\n      \"pmids\": [\"26113056\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"H2BC21 (also known as H2BE/H2BFQ/HIST2H2BE/H2B-GL105) is a histone H2B variant whose best-characterized isoform, expressed exclusively in olfactory neurons, is a replication-independent variant (H2BE) whose levels are regulated by sensory activity to control neuronal lifespan and olfactory receptor representation; the gene also produces alternative mRNAs by differential 3' end processing (cell-cycle-regulated vs. constitutive polyadenylated forms), and its expression must be tightly controlled for normal breast cancer cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"H2BC21 encodes a histone H2B variant whose best-characterized form, H2BE, is a replication-independent variant expressed exclusively in olfactory chemosensory neurons, where it links sensory activity to neuronal turnover [#0]. Sensory activity reduces H2BE expression, and the variant promotes neuronal cell death; reciprocal gain- and loss-of-function manipulations alter olfactory function and olfactory receptor representation, and H2BE carries post-translational modifications distinct from canonical H2B consistent with a role in modulating transcription [#0]. The gene generates two transcript classes by alternative 3' end processing: a short cell-cycle-dependent mRNA terminating after the histone dyad symmetry element and a longer constitutively expressed polyadenylated mRNA [#1]. Tightly controlled expression of this variant is also required for normal proliferation, as both overexpression and knockdown reduce breast cancer cell proliferation, and the gene is hypomethylated and overexpressed in estrogen deprivation-resistant lines [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established that the gene produces transcripts of two distinct architectures, defining it as both a cell-cycle-regulated and a constitutively expressed histone gene rather than a single replication-coupled histone.\",\n      \"evidence\": \"cDNA cloning, Northern blotting, chromosomal in situ hybridization, and cell-cycle synchronization mapping the gene to 1q21-1q23 paired with a functional H2A gene\",\n      \"pmids\": [\"1469070\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional consequence of the two transcript forms not tested\",\n        \"No protein-level characterization of the encoded variant\",\n        \"Single lab\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined H2BE as a replication-independent H2B variant restricted to olfactory neurons that couples sensory activity to neuronal lifespan and olfactory receptor representation, giving the variant a specific neurobiological function.\",\n      \"evidence\": \"Reciprocal gain- and loss-of-function mouse genetics with immunostaining, PTM profiling, and olfactory function assays\",\n      \"pmids\": [\"23240083\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Specific PTMs and their transcriptional targets not molecularly defined\",\n        \"Mechanism linking activity to H2BE downregulation unknown\",\n        \"Function outside olfactory neurons not addressed\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed that dosage of the variant is constrained for cell proliferation and that it is epigenetically deregulated in therapy-resistant breast cancer, extending its relevance beyond neurons.\",\n      \"evidence\": \"DNA methylation analysis, qRT-PCR, and reciprocal overexpression/siRNA knockdown with proliferation assays in breast cancer cell lines\",\n      \"pmids\": [\"26113056\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Molecular mechanism by which the variant constrains proliferation not defined\",\n        \"Chromatin incorporation in cancer cells not shown\",\n        \"Single lab, cell-line only\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How H2BE incorporation alters chromatin structure and transcription at the molecular level, and how its distinct PTMs are read, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"No structural or biochemical model of H2BE nucleosomes\",\n        \"Effector proteins recognizing its PTMs not identified\",\n        \"Mechanism connecting variant dosage to cell death and proliferation not established\"\n      ]\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:0000228\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"nucleosome\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}