H3C11

Summary

H3C11 (H3 clustered histone 11, HGNC:4771) is a protein-coding gene on chromosome 6p22.1, encoding Histone H3.1 (P68431). Core component of nucleosome. It is a selective cancer dependency (DepMap: 18.9% 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 is intronless and encodes a replication-dependent histone that is a member of the histone H3 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the small histone gene cluster on chromosome 6p22-p21.3.

Source: NCBI Gene 8354 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 17 total
• Cancer dependency (DepMap): dependent in 18.9% of screened cell lines
• MANE Select transcript: NM_003533

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4771
Approved symbol	H3C11
Name	H3 clustered histone 11
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Aliases	H3/f, H3.f
Ensembl gene	ENSG00000275379
Ensembl biotype	protein_coding
OMIM	602814
Entrez	8354

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000616365

RefSeq mRNA: 1 — MANE Select: NM_003533 NM_003533

CCDS: CCDS4636

Canonical transcript exons

ENST00000616365 — 1 exons

Exon	Start	End
ENSE00003747258	27871845	27872346

Expression profiles

Bgee: expression breadth broad, 96 present calls, max score 86.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 420.3556 / max 6865.5471, expressed in 1603 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72388	420.3556	1603

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	86.31	gold quality
bone marrow cell	CL:0002092	84.73	gold quality
tendon of biceps brachii	UBERON:0008188	77.71	gold quality
colonic epithelium	UBERON:0000397	71.87	gold quality
tendon	UBERON:0000043	68.04	gold quality
calcaneal tendon	UBERON:0003701	64.11	gold quality
pancreatic ductal cell	CL:0002079	59.85	silver quality
bone marrow	UBERON:0002371	58.60	gold quality
mucosa of transverse colon	UBERON:0004991	58.33	gold quality
ventricular zone	UBERON:0003053	58.10	gold quality
cerebellar vermis	UBERON:0004720	55.18	gold quality
tonsil	UBERON:0002372	55.07	gold quality
myocardium	UBERON:0002349	53.99	gold quality
corpus callosum	UBERON:0002336	53.87	gold quality
quadriceps femoris	UBERON:0001377	53.81	gold quality
vastus lateralis	UBERON:0001379	53.70	gold quality
ganglionic eminence	UBERON:0004023	53.68	gold quality
granulocyte	CL:0000094	53.24	gold quality
heart right ventricle	UBERON:0002080	52.59	gold quality
epithelial cell of pancreas	CL:0000083	51.17	gold quality
Brodmann (1909) area 46	UBERON:0006483	51.12	gold quality
embryo	UBERON:0000922	51.06	gold quality
frontal pole	UBERON:0002795	50.41	gold quality
middle frontal gyrus	UBERON:0002702	50.30	gold quality
paraflocculus	UBERON:0005351	50.18	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.18	gold quality
deltoid	UBERON:0001476	49.77	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
tibialis anterior	UBERON:0001385	49.20	silver quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6911	yes	112.09
E-ANND-3	no	1.74

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• Blocking of phosphorylation by O-GlcNAc on Ser 10 of H3 may result in gene silencing. Alternate phosphorylation and O-GlcNAc modification on Ser 10 in the histone H3 protein may provide an on/off switch to regulate expression of IE genes. (PMID:17668447)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:173552	ENSDARG00000051737
danio_rerio	si:ch1073-153i20.2	ENSDARG00000105345
danio_rerio	zgc:173552	ENSDARG00000110909
danio_rerio	si:ch211-113a14.27	ENSDARG00000111396
danio_rerio	si:ch211-113a14.20	ENSDARG00000112131
danio_rerio	zgc:173552	ENSDARG00000112175
danio_rerio	si:ch211-113a14.23	ENSDARG00000114334
drosophila_melanogaster	His3:CG33812	FBGN0053812
caenorhabditis_elegans		WBGENE00001876
caenorhabditis_elegans		WBGENE00001880
caenorhabditis_elegans		WBGENE00001883
caenorhabditis_elegans		WBGENE00001887
caenorhabditis_elegans		WBGENE00001891
caenorhabditis_elegans		WBGENE00001899
caenorhabditis_elegans		WBGENE00001901
caenorhabditis_elegans		WBGENE00001906
caenorhabditis_elegans		WBGENE00001914
caenorhabditis_elegans		WBGENE00001916
caenorhabditis_elegans		WBGENE00001919
caenorhabditis_elegans		WBGENE00001923
caenorhabditis_elegans		WBGENE00001929
caenorhabditis_elegans		WBGENE00001933
caenorhabditis_elegans		WBGENE00001937

Paralogs (20): CENPA (ENSG00000115163), H3-3B (ENSG00000132475), H3-3A (ENSG00000163041), H3-4 (ENSG00000168148), H3C13 (ENSG00000183598), H3-5 (ENSG00000188375), H3C12 (ENSG00000197153), H3C4 (ENSG00000197409), H3C14 (ENSG00000203811), H3C15 (ENSG00000203852), H3Y2 (ENSG00000268799), H3Y1 (ENSG00000269466), H3-7 (ENSG00000273213), H3C8 (ENSG00000273983), H3C6 (ENSG00000274750), H3C1 (ENSG00000275714), H3C7 (ENSG00000277775), H3C10 (ENSG00000278828), H3C2 (ENSG00000286522), H3C3 (ENSG00000287080)

Protein

Protein identifiers

Histone H3.1 — P68431 (reviewed: P68431)

Alternative names: Histone H3/a, Histone H3/b, Histone H3/c, Histone H3/d, Histone H3/f, Histone H3/h, Histone H3/i, Histone H3/j, Histone H3/k, Histone H3/l

All UniProt accessions (1): P68431

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.

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. Interacts with TONSL; CHAF1A; CHAF1B; MCM2 and DNAJC9. Interacts with NASP; NASP is a histone chaperone that stabilizes and maintains a soluble pool of Histone H3-H4 dimers.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription. Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3’ of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters. Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at ‘Lys-120’. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication. Phosphorylated at Thr-4 (H3T3ph) by VRK1. Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 or isoform M2 of PKM (PKM2) is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Thr-12 (H3T11ph) by chromatin-associated CHEK1 regulates the transcription of cell cycle regulatory genes by modulating acetylation of Lys-10 (H3K9ac). Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin. Monoubiquitinated at Lys-15 (H3K14ub), Lys-19 (H3K18ub) and Lys-24 (H3K23ub) by UHRF1 and HLTF at hemimethylated DNA sites following DNA replication, promoting recruitment of DNMT1 DNA methyltransferase and replication-coupled DNA methylation maintenance. Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression. 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. Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis. Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes. It gives a specific tag for epigenetic transcription activation. Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair. Serine ADP-ribosylation by PARP1 or PARP2 constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Serine ADP-ribosylation at Ser-11 (H3S10ADPr) promotes recruitment of CHD1L. H3S10ADPr is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac). Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation. H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription. Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons. H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.

Disease relevance. Glioma (GLM) [MIM:137800] Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. The gene represented in this entry is involved in disease pathogenesis. HIST1H3B mutations affecting residue Lys-28 involved in post-translational modifications of histone H3.1 are recurrent in malignant, aggressive gliomas including pediatric non-brain stem glioblastoma and diffuse intrinsic pontine glioma (DIPG). The mechanism through which mutations lead to tumorigenesis involves altered histone methylation, impaired regulation of Polycomb repressive complex 2 (PRC2) activity, and aberrant epigenetic regulation of gene expression. HIST1H3B or HIST1H3C mutations affecting residue Lys-37 of histone H3.1 are involved in the pathogenesis of pediatric undifferentiated soft tissue sarcomas. The mechanism through which mutations lead to tumorigenesis involves altered histones methylation with gain of global H3K27 methylation, altered Polycomb repressive complex 1 (PRC1) activity, aberrant epigenetic regulation of gene expression and impaired differentiation of mesenchimal progenitor cells.

Miscellaneous. This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).

Similarity. Belongs to the histone H3 family.

RefSeq proteins (1): NP_003524* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000164	Histone_H3/CENP-A	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily

Pfam: PF00125

UniProt features (146 total): modified residue 120, strand 8, sequence conflict 4, helix 4, cross-link 3, sequence variant 3, initiator methionine 1, chain 1, lipid moiety-binding region 1, region of interest 1

Structure

Experimental structures (PDB)

548 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5SVY	X-RAY DIFFRACTION	1.05
2V89	X-RAY DIFFRACTION	1.1
5SZC	X-RAY DIFFRACTION	1.19
5SZB	X-RAY DIFFRACTION	1.2
6BHD	X-RAY DIFFRACTION	1.25
4UP0	X-RAY DIFFRACTION	1.28
5WXH	X-RAY DIFFRACTION	1.3
5FFV	X-RAY DIFFRACTION	1.3
4L7X	X-RAY DIFFRACTION	1.35
6BHE	X-RAY DIFFRACTION	1.35
6BHI	X-RAY DIFFRACTION	1.4
3ASL	X-RAY DIFFRACTION	1.41
5TDR	X-RAY DIFFRACTION	1.42
2RI7	X-RAY DIFFRACTION	1.45
4X3K	X-RAY DIFFRACTION	1.45
6BHG	X-RAY DIFFRACTION	1.45
5GH9	X-RAY DIFFRACTION	1.45
3V43	X-RAY DIFFRACTION	1.47
5JIY	X-RAY DIFFRACTION	1.48
8IJ0	X-RAY DIFFRACTION	1.52
3RIY	X-RAY DIFFRACTION	1.55
5SVX	X-RAY DIFFRACTION	1.56
2VPG	X-RAY DIFFRACTION	1.6
4LK9	X-RAY DIFFRACTION	1.6
4Y6L	X-RAY DIFFRACTION	1.6
5T1I	X-RAY DIFFRACTION	1.6
5U2J	X-RAY DIFFRACTION	1.6
7CFP	X-RAY DIFFRACTION	1.6
7CFQ	X-RAY DIFFRACTION	1.6
6V41	X-RAY DIFFRACTION	1.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P68431-F1	86.95	0.71

Antibody-complex structures (SAbDab): 19 — 4YHP, 4YHZ, 7K5X, 7K5Y, 7K60, 7K61, 7K63, 7U0G, 7U0I, 7U0J, 8DK5, 8EVG, 8EVH, 8EVI, 8EVJ, 8SPS, 8SPU, 8SYP, 8VFX

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 (124): 5, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 5, 81, 87, 108, 116, 116, 123, 123, 123 …

Function

Pathways and Gene Ontology

Reactome pathways

48 pathways

ID	Pathway
R-HSA-1266695	Interleukin-7 signaling
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-3214815	HDACs deacetylate histones
R-HSA-3214841	PKMTs methylate histone lysines
R-HSA-3214842	HDMs demethylate histones
R-HSA-3214847	HATs acetylate histones
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-3247509	Chromatin modifying enzymes
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-68616	Assembly of the ORC complex at the origin of replication
R-HSA-73728	RNA Polymerase I Promoter Opening
R-HSA-73772	RNA Polymerase I Promoter Escape
R-HSA-8936459	RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs
R-HSA-9018519	Estrogen-dependent gene expression
R-HSA-912446	Meiotic recombination
R-HSA-9609690	HCMV Early Events
R-HSA-9610379	HCMV Late Events

MSigDB gene sets: 169 (showing top): REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_TELOMERE_ORGANIZATION, PUJANA_CHEK2_PCC_NETWORK, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, MODULE_99, MODULE_544, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, GOBP_CHROMATIN_REMODELING, GOBP_HETEROCHROMATIN_ORGANIZATION

GO Biological Process (5): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), telomere organization (GO:0032200), epigenetic regulation of gene expression (GO:0040029), gene expression (GO:0010467)

GO Molecular Function (5): DNA binding (GO:0003677), structural constituent of chromatin (GO:0030527), cadherin binding (GO:0045296), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (8): nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Chromatin modifying enzymes	5
Epigenetic regulation of gene expression	2
Cellular Senescence	2
Negative epigenetic regulation of rRNA expression	2
Positive epigenetic regulation of rRNA expression	2
Signaling by Interleukins	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Mitotic Prophase	1
Chromatin organization	1
Gene Silencing by RNA	1
Activation of HOX genes during differentiation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
chromatin	2
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
chromatin remodeling	1
regulation of gene expression	1
macromolecule biosynthetic process	1
nucleic acid binding	1
structural molecule activity	1
cell adhesion molecule binding	1
protein dimerization activity	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

448 interactions, top by confidence:

A	B	Type	Score
H3C1	CHAF1A	psi-mi:“MI:0914”(association)	0.910
NASP	H3C1	psi-mi:“MI:0915”(physical association)	0.910
SUZ12	EED	psi-mi:“MI:0914”(association)	0.910
H3C1	H4C16	psi-mi:“MI:0915”(physical association)	0.890
H4C16	H3C1	psi-mi:“MI:0407”(direct interaction)	0.890
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850
H3C1	RBBP4	psi-mi:“MI:0914”(association)	0.840
H3C1	DNAJC9	psi-mi:“MI:0915”(physical association)	0.810
NASP	H3C1	psi-mi:“MI:0915”(physical association)	0.780
H3C1	NASP	psi-mi:“MI:0915”(physical association)	0.780
H3C1	HAT1	psi-mi:“MI:0914”(association)	0.770
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
H3C1	MCM2	psi-mi:“MI:0915”(physical association)	0.710
H3C1	MCM2	psi-mi:“MI:0914”(association)	0.710
	KDM1A	psi-mi:“MI:0915”(physical association)	0.700
HTT	H3C1	psi-mi:“MI:0915”(physical association)	0.700

BioGRID (3102): HIST1H3A (Affinity Capture-Western), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3H (Two-hybrid), FBLIM1 (Two-hybrid), HIST1H3A (Reconstituted Complex), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), HIST1H3A (Biochemical Activity), KAT2B (Co-localization), HIST1H3A (Biochemical Activity)

ESM2 similar proteins: A1CP80, A1D240, A2QRR5, A3LXD5, A4RCX7, A5DFC5, A5DG57, P02299, P07041, P08898, P09988, P0CO04, P0CO05, P10651, P23753, P61832, P61834, P61835, P68431, P68432, P68433, P84227, P84228, P84229, P84230, P84231, P84233, P84234, P84235, P84236, P84237, P84238, P84239, Q0D0E8, Q0UY45, Q1E225, Q28D37, Q2UCQ0, Q4IER8, Q4QRF4

Diamond homologs: A1CP80, A1D240, A2QRR5, A2Y533, A3GHN6, A3LXD5, A4RCX7, A5DFC5, A5DG57, A5DWE2, A5E094, C0HL66, C0HL67, P02299, P02301, P07041, P08903, P09988, P0CO04, P0CO05, P10651, P23753, P59226, P61830, P61831, P61832, P61833, P61834, P61835, P61836, P68427, P68428, P68429, P68430, P68431, P68432, P68433, P69071, P69072, P69073

SIGNOR signaling

75 interactions.

A	Effect	B	Mechanism
AURKB	“down-regulates activity”	H3C1	phosphorylation
AURKB	“up-regulates activity”	H3C1	phosphorylation
AURKC	“up-regulates activity”	H3C1	phosphorylation
RPS6KA3	“down-regulates activity”	H3C1	phosphorylation
RPS6KA5	“down-regulates activity”	H3C1	phosphorylation
TGM2	unknown	H3C1	phosphorylation
PBK	unknown	H3C1	phosphorylation
MAML1	“down-regulates activity”	H3C1	acetylation
PIM1	“down-regulates activity”	H3C1	phosphorylation
VRK1	unknown	H3C1	phosphorylation
MAPK14	unknown	H3C1	phosphorylation
PRKCD	“up-regulates activity”	H3C1	phosphorylation
PIM	“down-regulates activity”	H3C1	phosphorylation
KDM6A	“down-regulates activity”	H3C1	demethylation
KDM6B	“down-regulates activity”	H3C1	demethylation
CTNNB1	“up-regulates activity”	H3C1
“Polycomb repressive complex 2”	“up-regulates activity”	H3C1	methylation
KDM4B	“down-regulates activity”	H3C1	demethylation
KDM4C	“down-regulates activity”	H3C1	demethylation
SETDB2	“up-regulates activity”	H3C1	methylation
KDM5A	“up-regulates activity”	H3C1	demethylation
KDM5B	“up-regulates activity”	H3C1	demethylation
KDM5C	“up-regulates activity”	H3C1	demethylation
KDM5D	“up-regulates activity”	H3C1	demethylation
“Set1-Ash2 HMT complex”	“down-regulates activity”	H3C1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 123 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
Regulation of PTEN gene transcription	9	19.4×	4e-08
Defective pyroptosis	10	18.9×	1e-08
Negative Regulation of CDH1 Gene Transcription	13	18.8×	7e-11
PRC2 methylates histones and DNA	10	18.4×	1e-08
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	10	18.4×	1e-08
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	5	18.1×	8e-05
ChAHP complex assembly	8	17.8×	4e-07
Transcriptional Regulation by E2F6	5	17.6×	9e-05

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	10	24.6×	3e-09
nucleosome assembly	17	23.0×	8e-16
chromatin organization	12	11.4×	1e-07
chromatin remodeling	15	10.5×	3e-09
DNA replication	6	9.5×	5e-03
DNA repair	13	8.0×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

103 predictions. Top by Δscore:

Variant	Effect	Δscore
6:27872147:T:TA	donor_gain	0.8100
6:27872120:G:C	donor_gain	0.7500
6:27872124:C:A	donor_gain	0.7200
6:27872204:T:TA	donor_gain	0.7000
6:27872212:C:CT	donor_gain	0.7000
6:27872101:A:AC	donor_gain	0.6400
6:27872102:C:CC	donor_gain	0.6400
6:27872097:CCGT:C	donor_loss	0.5800
6:27872098:CGTA:C	donor_loss	0.5800
6:27872099:GT:G	donor_loss	0.5800
6:27872100:T:TG	donor_loss	0.5800
6:27872102:CCA:C	donor_loss	0.5800
6:27872213:C:CT	donor_gain	0.5800
6:27872102:CCAAG:C	donor_gain	0.5700
6:27872119:AGCTT:A	donor_gain	0.5600
6:27872103:C:G	donor_loss	0.5500
6:27871907:ATGC:A	donor_gain	0.5400
6:27872044:A:AC	donor_gain	0.5400
6:27871917:C:A	donor_gain	0.5300
6:27872032:T:TA	donor_gain	0.5300
6:27872135:G:C	donor_gain	0.5000
6:27872096:CCCG:C	donor_loss	0.4800
6:27872049:C:CT	donor_gain	0.4700
6:27872042:CCA:C	donor_gain	0.4500
6:27872083:T:TA	donor_gain	0.4500
6:27872096:C:CA	donor_gain	0.4500
6:27871916:C:CA	donor_gain	0.4400
6:27872043:CA:C	donor_gain	0.4400
6:27872107:CG:C	acceptor_gain	0.4400
6:27872132:G:C	donor_gain	0.4200

AlphaMissense

862 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000243106 (6:27873406 G>A,T), RS1000531261 (6:27873562 A>C,G), RS1000620583 (6:27871918 C>G), RS1000737771 (6:27871712 T>C), RS1002291307 (6:27873086 A>G), RS1002355328 (6:27872666 C>T), RS1002363655 (6:27874090 C>G,T), RS1002689025 (6:27873675 C>G), RS1002741078 (6:27874020 G>C,T), RS1003016064 (6:27871698 A>G), RS1004193627 (6:27872878 C>T), RS1004256425 (6:27874018 T>C), RS1004715817 (6:27872648 G>C), RS1006269315 (6:27873147 A>T), RS1008216616 (6:27871986 C>G)

Disease associations

OMIM: gene MIM:602814 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST004521_112	Autism spectrum disorder or schizophrenia	3.000000e-26
GCST004521_115	Autism spectrum disorder or schizophrenia	3.000000e-16
GCST004521_116	Autism spectrum disorder or schizophrenia	3.000000e-16
GCST004521_166	Autism spectrum disorder or schizophrenia	4.000000e-24
GCST004521_22	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_23	Autism spectrum disorder or schizophrenia	2.000000e-11
GCST004521_6	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_73	Autism spectrum disorder or schizophrenia	8.000000e-11
GCST008921_6	Asthma and major depressive disorder	1.000000e-09
GCST010002_50	Refractive error	4.000000e-34
GCST010142_16	Fish- and plant-related diet	2.000000e-10
GCST010142_19	Fish- and plant-related diet	4.000000e-10
GCST010142_34	Fish- and plant-related diet	7.000000e-09
GCST010142_35	Fish- and plant-related diet	8.000000e-09
GCST010142_42	Fish- and plant-related diet	1.000000e-08
GCST010142_7	Fish- and plant-related diet	3.000000e-12
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16
GCST012228_154	Waist-hip index	7.000000e-10
GCST012230_277	Waist-to-hip ratio adjusted for BMI	6.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

Binding affinities (BindingDB)

3 measured of 6 human assays (6 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-hydroxy-3-(2-phenethyl-1-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazol-5-yl)acrylamide	EC50	500 nM	US-10201527: Benzimidazole derivatives: preparation and pharmaceutical applications
3-(1-(3-(dimethylamino)-2,2-dimethylpropyl)-2-phenethyl-1H-benzo[d]imidazol-5-yl)-N-hydroxyacrylamide	EC50	1100 nM	US-10201527: Benzimidazole derivatives: preparation and pharmaceutical applications
N-hydroxy-3-(2-phenethyl-1-(3,4,5-trimethoxybenzyl)-1H-benzo[d]imidazol-5-yl)acrylamide	EC50	1700 nM	US-10201527: Benzimidazole derivatives: preparation and pharmaceutical applications

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Air Pollutants	increases expression, affects cotreatment, increases abundance	2
afuresertib	decreases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
cobaltous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
2-palmitoylglycerol	increases expression	1
Acrolein	increases expression, increases abundance, affects cotreatment	1
Amiodarone	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Folic Acid	affects cotreatment, decreases expression	1
Mercury	increases expression	1
Methotrexate	affects cotreatment, decreases expression	1
Ozone	affects cotreatment, increases expression, increases abundance	1
Plant Oils	increases expression	1
Testosterone	decreases expression	1
Tretinoin	decreases expression	1
Cadmium Chloride	increases expression, increases abundance	1
Lactic Acid	decreases expression	1
Particulate Matter	increases abundance, increases expression	1
Volatile Organic Compounds	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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