H2BC21

Summary

H2BC21 (H2B clustered histone 21, HGNC:4760) is a protein-coding gene on chromosome 1q21.2, encoding Histone H2B type 2-E (Q16778). Core component of nucleosome. It is a selective cancer dependency (DepMap: 76.0% of cell lines).

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene encodes a replication-dependent histone that is a member of the histone H2B family, and generates two transcripts through the use of the conserved stem-loop termination motif, and the polyA addition motif. The protein has antibacterial and antifungal antimicrobial activity.

Source: NCBI Gene 8349 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 18 total
• Cancer dependency (DepMap): dependent in 76.0% of screened cell lines
• MANE Select transcript: NM_003528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4760
Approved symbol	H2BC21
Name	H2B clustered histone 21
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	H2B/q, H2B.1, H2BE, H2B-GL105
Ensembl gene	ENSG00000184678
Ensembl biotype	protein_coding
OMIM	601831
Entrez	8349

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369155

RefSeq mRNA: 1 — MANE Select: NM_003528 NM_003528

CCDS: CCDS936

Canonical transcript exons

ENST00000369155 — 1 exons

Exon	Start	End
ENSE00001448926	149884459	149886682

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 96.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 264.2373 / max 3834.0868, expressed in 1817 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14257	1271.8716	1826
14258	264.2373	1817
14256	0.7431	290

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	96.19	gold quality
monocyte	CL:0000576	95.55	gold quality
heart left ventricle	UBERON:0002084	95.32	gold quality
cardiac ventricle	UBERON:0002082	95.29	gold quality
mononuclear cell	CL:0000842	95.18	gold quality
right uterine tube	UBERON:0001302	94.94	gold quality
prostate gland	UBERON:0002367	94.90	gold quality
ganglionic eminence	UBERON:0004023	94.71	gold quality
leukocyte	CL:0000738	94.43	gold quality
lower esophagus mucosa	UBERON:0035834	94.09	gold quality
apex of heart	UBERON:0002098	94.05	gold quality
left ventricle myocardium	UBERON:0006566	94.03	gold quality
endometrium epithelium	UBERON:0004811	93.78	gold quality
gastrocnemius	UBERON:0001388	93.76	gold quality
muscle of leg	UBERON:0001383	93.44	gold quality
heart	UBERON:0000948	93.02	gold quality
tibialis anterior	UBERON:0001385	93.00	gold quality
olfactory bulb	UBERON:0002264	92.85	gold quality
right atrium auricular region	UBERON:0006631	92.82	gold quality
muscle organ	UBERON:0001630	92.67	gold quality
skin of abdomen	UBERON:0001416	92.54	gold quality
cardiac atrium	UBERON:0002081	92.26	gold quality
skin of leg	UBERON:0001511	91.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.81	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.78	gold quality
pylorus	UBERON:0001166	91.61	gold quality
deltoid	UBERON:0001476	91.50	gold quality
vagina	UBERON:0000996	91.49	gold quality
vastus lateralis	UBERON:0001379	91.48	gold quality
quadriceps femoris	UBERON:0001377	91.44	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.32
E-GEOD-99795	no	116.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting H2BC21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6715A-3P	99.83	68.05	1473
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 30)

• Histone H2B antimicrobial peptides participate in the colonic defense against bacteria and fungi. (PMID:12860195)
• Protein phosphatase 2C gamma binds to/dephosporylates histone 2b to affect chromatin function. (PMID:17074886)
• The 2 MDa GCN5 HAT-containing metazoan TFTC/STAGA complexes contain a histone H2A and H2B deubiquitinase activity. (PMID:18206972)
• A redox-modulated direct p38/GAPDH-Oct-1 interaction nucleates the occupancy of the H2B promoter by the OCA-S complex, in which p36/LDH plays a critical role in the hierarchical organization of the complex. (PMID:18682386)
• These studies establish the natural H2B ubiquitylation factors in human cells and also detail the mechanistic basis for H2B ubiquitylation and function during transcription (PMID:19410543)
• NO-mediated H2B gene repression depends on modifications of endogenous PPAR ligands. (PMID:19425504)
• these data point at acetylation of Lysine 120 of H2B as an early mark of poised or active state and establish a temporal sequence between acetylation and mono-ubiquitination of this H2B residue. (PMID:21739721)
• Studies indicate that H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. (PMID:21827756)
• H2B and H4 histones were mobilized during herpes simplex virus 1 infection and became available to bind to viral genomes. (PMID:21994445)
• after H2B monoubiquitylation H2B is largely positioned at the exon-intron boundaries of highly expressed exons, and it demonstrates increased occupancy in skipped exons compared with flanking exons in the human genome (PMID:22421545)
• cancerous cells in the tumor specimens. Taken together, our data suggest that glucose deficiency and loss of uH2B are novel properties of cancer cells in vivo, which may represent important regulatory mechanisms of tumorigenesis (PMID:22615809)
• Autoimmunity to isoAsp histone H2B suggests that this form of the autoantigen may be critical in the induction of anti-histone autoantibodies in human SLE. (PMID:22967069)
• Knockdown of EZH2 increased the ubiquitination level of H2BK120. (PMID:24339737)
• H2B K34 ubiquitylation by the MOF-MSL complex is part of the protein networks involved in early steps of transcription elongation. (PMID:24837678)
• Results show that the cotranscriptional ubiquitylation of histone H2B suggests that it may be more intimately involved in ongoing nucleosome turnover in the wake of Pol II. (PMID:25049226)
• analysis of a functional hotspot on ubiquitin that is required for the stimulation of human Dot1 (PMID:26240340)
• Study provides the first observation of the proteolytic processing of histones H2B and H3 in human hepatocytes where four different clipping sites were localized in H3 and one in H2B. (PMID:26424599)
• Gene expression analysis identified deregulation of histone H2A and H2B genes in all four cell lines ;histone pathways are associated with epirubicin resistance (PMID:26852132)
• All cases with ARID1A expression are overlapped with H2B high expression. Among 15 cases with ARID1A and H2B coexpression, 13 are invasive ductal carcinoma and 2 are mucinous carcinoma. Our results indicate that ARID1A gene may be involved in carcinogenesis of some subtypes of breast cancer. (PMID:26904685)
• The 2.7-A-resolution crystal structure of the human YL1-H2A.Z-H2B complex shows that YL1 binding, similarly to ANP32E binding, triggers an extension of the H2A.Z alphaC helix. (PMID:26974126)
• CRL4(Wdr70) regulates H2B monoubiquitination and facilitates Exo1-dependent DNA repair resection. (PMID:27098497)
• Within the nucleus, PKC-theta; catalytic activity maintains the Ser536 phosphorylation on the p65 subunit of NF-kappaB (also known as RelA) and can directly influence chromatin accessibility at transcriptional memory genes by regulating H2B deposition. (PMID:27149922)
• we found an excess of mutations in genes encoding histone H2A and H2B, as well as significant amplification of the segment of chromosome 6p harboring the histone gene cluster containing these genes.We also found frequent deletions of the genes TP53 and MBD3 (a member with CHD4 of the nucleosome remodeling deacetylase complex). (PMID:27791010)
• Findings uncover a novel function of let-7 miRNAs as regulators of H2B ubiquitylation, suggesting an additional mechanism whereby these miRNAs can exert their tumor-suppressive effects. (PMID:28604753)
• hese results suggest that TRAIP is a novel regulator of H2B monoubiquitination in DNA damage response and cancer development in lung adenocarcinoma. (PMID:30942468)
• Cancer-associated histone mutation H2BG53D disrupts DNA-histone octamer interaction and promotes oncogenic phenotypes. (PMID:32296031)
• The H2BG53D oncohistone directly upregulates ANXA3 transcription and enhances cell migration in pancreatic ductal adenocarcinoma. (PMID:32606294)
• HIV-Infected Patients: Cross Site-Specific Hydrolysis of H2a and H2b Histones and Myelin Basic Protein with Antibodies against These Three Proteins. (PMID:33143355)
• Nucleotide variation in histone H2BL drives crossalk of histone modification and promotes tumour cell proliferation by upregulating c-Myc. (PMID:33515561)
• Overexpression of ring finger protein 20 inhibits the progression of liver fibrosis via mediation of histone H2B lysine 120 ubiquitination. (PMID:33575967)

Cross-species orthologs

0 orthologs

Paralogs (21): H2BW2 (ENSG00000101812), H2BW1 (ENSG00000123569), H2BC11 (ENSG00000124635), H2BC1 (ENSG00000146047), H2BC5 (ENSG00000158373), H2BC4 (ENSG00000180596), H2BC13 (ENSG00000185130), H2BC26 (ENSG00000196890), H2BC12 (ENSG00000197903), H2BC18 (ENSG00000203814), H2BC15 (ENSG00000233822), H2BC12L (ENSG00000234289), H2BC14 (ENSG00000273703), H2BC8 (ENSG00000273802), H2BC6 (ENSG00000274290), H2BC17 (ENSG00000274641), H2BC9 (ENSG00000275713), H2BC3 (ENSG00000276410), H2BC7 (ENSG00000277224), H2BC10 (ENSG00000278588), H2BK1 (ENSG00000285480)

Protein

Protein identifiers

Histone H2B type 2-E — Q16778 (reviewed: Q16778)

Alternative names: H2B-clustered histone 21, Histone H2B-GL105, Histone H2B.q

All UniProt accessions (1): Q16778

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 ‘Lys-4’ (H3K4me) and ‘Lys-79’ (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 ‘Lys-4’ and ‘Lys-79’ methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons. Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription. Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination. GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes. ADP-ribosylated by PARP1 or PARP2 on Ser-7 (H2BS6ADPr) in response to DNA damage. H2BS6ADPr promotes recruitment of CHD1L. Mono-ADP-ribosylated on Glu-3 (H2BE2ADPr) by PARP3 in response to single-strand breaks. Poly ADP-ribosylation on Glu-36 (H2BE35ADPr) by PARP1 regulates adipogenesis: it inhibits phosphorylation at Ser-37 (H2BS36ph), thereby blocking expression of pro-adipogenetic genes. Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.

Similarity. Belongs to the histone H2B family.

RefSeq proteins (1): NP_003519* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000558	Histone_H2B	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR055333	HISTONE_H2B_site	Conserved_site

Pfam: PF00125

UniProt features (108 total): modified residue 91, helix 4, cross-link 4, strand 3, initiator methionine 1, chain 1, sequence conflict 1, region of interest 1, compositionally biased region 1, glycosylation site 1

Structure

Experimental structures (PDB)

40 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8UQA	X-RAY DIFFRACTION	2.05
8UQ9	X-RAY DIFFRACTION	2.3
8UQ8	X-RAY DIFFRACTION	2.34
6KBB	X-RAY DIFFRACTION	2.37
8UQB	X-RAY DIFFRACTION	2.48
6A7U	X-RAY DIFFRACTION	2.6
7U0G	ELECTRON MICROSCOPY	2.6
7U0I	ELECTRON MICROSCOPY	2.6
8SYP	ELECTRON MICROSCOPY	2.6
4NFT	X-RAY DIFFRACTION	2.61
8UQC	X-RAY DIFFRACTION	2.61
8EVI	ELECTRON MICROSCOPY	2.64
7U0J	ELECTRON MICROSCOPY	2.7
8DK5	ELECTRON MICROSCOPY	2.71
8EVG	ELECTRON MICROSCOPY	2.75
6M4G	ELECTRON MICROSCOPY	2.8
8SPU	ELECTRON MICROSCOPY	2.8
8EVH	ELECTRON MICROSCOPY	2.85
8H1T	ELECTRON MICROSCOPY	3
8SPS	ELECTRON MICROSCOPY	3
7EA8	ELECTRON MICROSCOPY	3.1
9GCG	ELECTRON MICROSCOPY	3.43
9YM8	ELECTRON MICROSCOPY	3.43
9YMF	ELECTRON MICROSCOPY	3.45
9GEV	ELECTRON MICROSCOPY	3.47
9YL3	ELECTRON MICROSCOPY	3.5
9GE4	ELECTRON MICROSCOPY	3.52
9GFB	ELECTRON MICROSCOPY	3.55
8UQE	X-RAY DIFFRACTION	3.56
9YLE	ELECTRON MICROSCOPY	3.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16778-F1	88.11	0.68

Antibody-complex structures (SAbDab): 11 — 7U0G, 7U0I, 7U0J, 8DK5, 8EVG, 8EVH, 8EVI, 8EVJ, 8SPS, 8SPU, 8SYP

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (95): 6, 6, 6, 6, 7, 12, 12, 12, 12, 12, 12, 13, 13, 13, 15, 16, 16, 16, 16, 17 …

Glycosylation sites (1): 113

Function

Pathways and Gene Ontology

Reactome pathways

57 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-427359	SIRT1 negatively regulates rRNA expression
R-HSA-427389	ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression
R-HSA-427413	NoRC negatively regulates rRNA expression
R-HSA-5250924	B-WICH complex positively regulates rRNA expression
R-HSA-5334118	DNA methylation
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-5617472	Activation of anterior HOX genes in hindbrain development during early embryogenesis
R-HSA-5625886	Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3
R-HSA-5689880	Ub-specific processing proteases
R-HSA-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends
R-HSA-606279	Deposition of new CENPA-containing nucleosomes at the centromere
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-69473	G2/M DNA damage checkpoint

MSigDB gene sets: 377 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, REACTOME_MEIOTIC_RECOMBINATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, KOBAYASHI_EGFR_SIGNALING_24HR_UP, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, FISCHER_G1_S_CELL_CYCLE, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, MODULE_45, GOZGIT_ESR1_TARGETS_DN, RIZKI_TUMOR_INVASIVENESS_3D_DN

GO Biological Process (6): innate immune response in mucosa (GO:0002227), nucleosome assembly (GO:0006334), antibacterial humoral response (GO:0019731), defense response to Gram-positive bacterium (GO:0050830), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), defense response to bacterium (GO:0042742)

GO Molecular Function (4): DNA binding (GO:0003677), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (7): nucleosome (GO:0000786), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Cellular Senescence	3
Depyrimidination	2
Depurination	2
Epigenetic regulation of gene expression	2
Chromatin modifying enzymes	2
Negative epigenetic regulation of rRNA expression	2
Positive epigenetic regulation of rRNA expression	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Mitotic Prophase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
antimicrobial humoral response	2
defense response to bacterium	2
chromatin	2
cellular anatomical structure	2
mucosal immune response	1
innate immune response	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
defense response	1
response to bacterium	1
nucleic acid binding	1
structural molecule activity	1
protein dimerization activity	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4972 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H2BC21	H2AC20	Q16777	999
H2BC21	H3C1	P02295	999
H2BC21	H2AC19	P20670	999
H2BC21	H3-3A	P06351	998
H2BC21	H2AZ1	P0C0S5	998
H2BC21	H3C14	Q71DI3	998
H2BC21	H3-5	Q6NXT2	998
H2BC21	H3-4	Q16695	998
H2BC21	H3-7	Q5TEC6	998
H2BC21	H4C16	P02304	997
H2BC21	H4C7	Q99525	997
H2BC21	H1-0	P07305	994
H2BC21	H2AX	P16104	986
H2BC21	H1-1	Q02539	983
H2BC21	H1-5	P16401	976

IntAct

238 interactions, top by confidence:

A	B	Type	Score
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
H1-2	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H1-4	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H2AZ1	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H1-0	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	H4C16	psi-mi:“MI:0915”(physical association)	0.560
SSRP1	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
PWWP2A	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H2AC14	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
ZMYM3	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
NSD1	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
PHF2	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	HMGA1	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	H3C13	psi-mi:“MI:0915”(physical association)	0.560
PRPF8	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
INCENP	H2BC21	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	AP2M1	psi-mi:“MI:0915”(physical association)	0.560
	H2BC21	psi-mi:“MI:0407”(direct interaction)	0.440
WEE1	H2BC21	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
H2BC21	HNRNPK	psi-mi:“MI:0915”(physical association)	0.400
H2BC21	EDN1	psi-mi:“MI:0915”(physical association)	0.400
H2BC21	OSBPL8	psi-mi:“MI:0915”(physical association)	0.400
CRYBG1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
TMEM135	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
H1-1	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
HMGN2	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
IGSF3	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
DDX52	H2BC21	psi-mi:“MI:0915”(physical association)	0.400
SSB	H2BC21	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (1072): HIST2H2BE (Biochemical Activity), HIST2H2BE (Biochemical Activity), HIST2H2BE (Biochemical Activity), HIST2H2BE (Affinity Capture-MS), HIST2H2BE (Affinity Capture-MS), HIST2H2BE (Affinity Capture-Western), HIST2H2BE (Biochemical Activity), HIST2H2BE (Biochemical Activity), HIST2H2BE (Biochemical Activity), HIST2H2BE (Biochemical Activity), CDK9 (Co-fractionation), POLR2A (Co-fractionation), HIST2H2BE (Reconstituted Complex), HIST2H2BE (Affinity Capture-MS), HIST2H2BE (Affinity Capture-MS)

ESM2 similar proteins: A0A2R8Y619, O97484, P02284, P02285, P02286, P02287, P02288, P04255, P04913, P07794, P07795, P0C1H4, P16888, P16889, P16890, P19374, P21897, P23527, P27326, P30757, P33778, P35067, P35068, P35069, P48557, P57053, P62807, P62808, P70696, P83863, Q00715, Q00729, Q16778, Q27894, Q32L48, Q5QNW6, Q5R893, Q5RCP8, Q64475, Q64478

Diamond homologs: A0A2R8Y619, A2WKT1, A2WKT4, A2WWU2, A2XF66, A2YWI3, A3AGM4, O22582, O60814, O65819, P02281, P02283, P02284, P02285, P02286, P02287, P02288, P02289, P02290, P04255, P06145, P06899, P06900, P07794, P07795, P0C1H3, P0C1H4, P0C1H5, P10853, P10854, P14001, P16888, P16889, P16890, P17271, P19374, P21897, P23527, P27326, P27807

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
IRX1	“down-regulates quantity by repression”	H2BC21	“transcriptional regulation”
SLBP	“up-regulates quantity by expression”	H2BC21	“translation regulation”
MSL2	“down-regulates activity”	H2BC21	monoubiquitination
MSL1	“down-regulates activity”	H2BC21	monoubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 210 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of Senescence-Associated Heterochromatin Foci (SAHF)	6	32.0×	7e-06
Packaging Of Telomere Ends	7	12.2×	1e-04
Recognition and association of DNA glycosylase with site containing an affected purine	7	11.3×	2e-04
Cleavage of the damaged purine	7	11.3×	2e-04
Condensation of Prophase Chromosomes	9	11.2×	2e-05
FXIIa activates plasma kallikrein-kinin system	8	11.0×	6e-05
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	7	10.2×	2e-04
Cleavage of the damaged pyrimidine	7	10.2×	2e-04

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	6	36.8×	4e-06
chromosome condensation	6	27.6×	2e-05
nucleosome assembly	15	11.5×	4e-09
heterochromatin formation	7	9.8×	2e-03
chromatin organization	10	5.4×	4e-03
chromatin remodeling	11	4.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

18 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

99 predictions. Top by Δscore:

Variant	Effect	Δscore
1:149886262:A:AC	donor_gain	0.9100
1:149886263:C:CC	donor_gain	0.9100
1:149885885:T:C	acceptor_gain	0.8100
1:149885885:T:TC	acceptor_gain	0.7800
1:149885854:T:TG	acceptor_gain	0.7300
1:149885849:TTCTC:T	acceptor_gain	0.7200
1:149885850:TCTCT:T	acceptor_gain	0.7200
1:149885851:CTCTT:C	acceptor_gain	0.7100
1:149885853:C:G	acceptor_gain	0.6900
1:149886280:TGGTG:T	donor_gain	0.6800
1:149885855:T:G	acceptor_gain	0.6700
1:149885526:CATT:C	acceptor_gain	0.6100
1:149885996:T:A	acceptor_gain	0.5800
1:149885542:CAT:C	acceptor_gain	0.5500
1:149885881:CGTTT:C	acceptor_gain	0.5200
1:149885775:GCTGC:G	acceptor_gain	0.4900
1:149885995:C:A	acceptor_gain	0.4800
1:149885994:GC:G	acceptor_gain	0.4500
1:149886255:GGGAC:G	donor_loss	0.4400
1:149886256:GGAC:G	donor_loss	0.4400
1:149886257:GAC:G	donor_loss	0.4400
1:149886258:AC:A	donor_loss	0.4400
1:149886259:CTC:C	donor_loss	0.4400
1:149886260:T:TA	donor_loss	0.4400
1:149886261:CAC:C	donor_loss	0.4400
1:149886263:C:A	donor_loss	0.4400
1:149886264:T:C	donor_gain	0.4400
1:149885348:CA:C	acceptor_gain	0.4300
1:149885854:T:C	acceptor_gain	0.4200
1:149885776:CTGCT:C	acceptor_gain	0.4100

AlphaMissense

813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:149886285:A:T	V119D	1.000
1:149886289:C:G	A118P	1.000
1:149886290:C:A	K117N	1.000
1:149886290:C:G	K117N	1.000
1:149886292:T:C	K117E	1.000
1:149886297:C:A	G115V	1.000
1:149886297:C:T	G115D	1.000
1:149886298:C:A	G115C	1.000
1:149886298:C:G	G115R	1.000
1:149886298:C:T	G115S	1.000
1:149886309:G:T	A111D	1.000
1:149886310:C:G	A111P	1.000
1:149886311:G:C	H110Q	1.000
1:149886311:G:T	H110Q	1.000
1:149886313:G:C	H110D	1.000
1:149886313:G:T	H110N	1.000
1:149886314:C:A	K109N	1.000
1:149886314:C:G	K109N	1.000
1:149886318:G:T	A108D	1.000
1:149886321:A:G	L107P	1.000
1:149886321:A:T	L107Q	1.000
1:149886325:C:T	E106K	1.000
1:149886327:C:A	G105V	1.000
1:149886327:C:T	G105D	1.000
1:149886328:C:A	G105C	1.000
1:149886328:C:G	G105R	1.000
1:149886339:A:G	L101P	1.000
1:149886339:A:T	L101Q	1.000
1:149886348:G:T	A98D	1.000
1:149886349:C:G	A98P	1.000

dbSNP variants (sampled 300 via entrez): RS1002085119 (1:149885572 G>A), RS1004208294 (1:149886803 C>T), RS1005621517 (1:149885489 G>C), RS1008980388 (1:149887855 C>T), RS1010395410 (1:149884201 C>T), RS1010862953 (1:149884546 G>T), RS1012800960 (1:149888479 C>T), RS1014554334 (1:149887856 G>A), RS1015832667 (1:149886687 G>A,C), RS1016899751 (1:149885510 G>C), RS1020749141 (1:149886077 T>A,C), RS1020781430 (1:149885606 G>A), RS1021831165 (1:149884247 A>C,G), RS1022220927 (1:149888615 T>C), RS1024103141 (1:149888270 T>A)

Disease associations

OMIM: gene MIM:601831 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010241_209	Apolipoprotein A1 levels	1.000000e-09
GCST010242_127	HDL cholesterol levels	1.000000e-12

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

91 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	decreases expression, increases expression	11
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation, increases expression	8
sodium arsenite	decreases expression, increases expression	4
Acetaminophen	increases expression	3
Benzo(a)pyrene	increases expression	3
Formaldehyde	increases expression	3
Silicon Dioxide	increases expression	3
Cyclosporine	increases expression	3
bisphenol A	decreases expression	2
mercuric bromide	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, decreases expression, affects expression	2
Doxorubicin	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression, increases expression	1
OTX015	increases expression	1
bisphenol F	increases expression	1
beauvericin	affects cotreatment, increases expression	1
propionaldehyde	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
zinc chromate	increases abundance, increases expression	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8H3	Abcam HCT 116 H2BC21 KO	Cancer cell line	Male
CVCL_B9JD	Abcam A-549 H2BC21 KO	Cancer cell line	Male
CVCL_D2FI	Abcam MCF-7 HIST2H2BE KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.