H3C4

Summary

H3C4 (H3 clustered histone 4, HGNC:4767) is a protein-coding gene on chromosome 6p22.2, encoding Histone H3.1 (P68431). Core component of nucleosome.

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 large histone gene cluster on chromosome 6.

Source: NCBI Gene 8351 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_001376937

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4767
Approved symbol	H3C4
Name	H3 clustered histone 4
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H3/b
Ensembl gene	ENSG00000197409
Ensembl biotype	protein_coding
OMIM	602811
Entrez	8351

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000356476, ENST00000718271

RefSeq mRNA: 2 — MANE Select: NM_001376937 NM_001376937, NM_003530

CCDS: CCDS4590

Canonical transcript exons

ENST00000356476 — 1 exons

Exon	Start	End
ENSE00004034585	26196784	26197286

Expression profiles

Bgee: expression breadth ubiquitous, 132 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 703.2818 / max 20583.2910, expressed in 1806 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72325	703.2818	1806
72319	236.8353	1803
72323	4.6485	991
72322	1.4224	525
72321	0.1132	35
203915	0.0891	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	98.85	gold quality
adrenal tissue	UBERON:0018303	91.08	gold quality
bone marrow	UBERON:0002371	89.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.70	gold quality
lower esophagus mucosa	UBERON:0035834	77.56	gold quality
colonic epithelium	UBERON:0000397	76.82	gold quality
tonsil	UBERON:0002372	74.76	gold quality
calcaneal tendon	UBERON:0003701	72.08	gold quality
corpus callosum	UBERON:0002336	70.36	gold quality
blood	UBERON:0000178	70.07	gold quality
ventricular zone	UBERON:0003053	68.40	gold quality
mucosa of transverse colon	UBERON:0004991	67.37	gold quality
granulocyte	CL:0000094	63.82	gold quality
vagina	UBERON:0000996	62.85	gold quality
stromal cell of endometrium	CL:0002255	61.03	gold quality
right adrenal gland	UBERON:0001233	58.94	gold quality
right adrenal gland cortex	UBERON:0035827	58.57	gold quality
uterine cervix	UBERON:0000002	58.23	gold quality
esophagus mucosa	UBERON:0002469	57.23	gold quality
prostate gland	UBERON:0002367	57.15	gold quality
spleen	UBERON:0002106	56.98	gold quality
liver	UBERON:0002107	56.17	gold quality
leukocyte	CL:0000738	55.64	gold quality
right lobe of liver	UBERON:0001114	55.57	gold quality
adrenal gland	UBERON:0002369	54.93	gold quality
monocyte	CL:0000576	54.65	gold quality
lung	UBERON:0002048	53.99	gold quality
urinary bladder	UBERON:0001255	53.63	gold quality
esophagus	UBERON:0001043	53.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	864.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• HIST1H3D expression in the bone marrow, peripheral blood, and primary tumor of stage IV patients is higher than that in stage I patients. (PMID:24097871)
• HIST1H3D is highly expressed in lung cancer cell lines and tissues, and may be important in cell proliferation, apoptosis and cell cycle progression, and is implicated as a potential therapeutic target for lung cancer. (PMID:28112369)
• Fucoxanthin may inhibit cervical cancer cell proliferation via downregulation of HIST1H3D. (PMID:33086884)

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), H3C14 (ENSG00000203811), H3C15 (ENSG00000203852), H3Y2 (ENSG00000268799), H3Y1 (ENSG00000269466), H3-7 (ENSG00000273213), H3C8 (ENSG00000273983), H3C6 (ENSG00000274750), H3C11 (ENSG00000275379), 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 (2): NP_001363866, NP_003521 (=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: 208 (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, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOZGIT_ESR1_TARGETS_DN, GOBP_TELOMERE_ORGANIZATION, CAGCTG_AP4_Q5, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, MODULE_256

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

122 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26197265:CCCTG:C	acceptor_gain	1.0000
6:26197266:CCTGC:C	acceptor_gain	1.0000
6:26197267:CTG:C	acceptor_gain	1.0000
6:26197266:CCTG:C	acceptor_loss	0.9900
6:26197268:TG:T	acceptor_gain	0.9900
6:26197268:TGC:T	acceptor_loss	0.9900
6:26197269:GCT:G	acceptor_loss	0.9900
6:26197270:C:CC	acceptor_gain	0.9900
6:26197271:T:C	acceptor_loss	0.9900
6:26197263:AACCC:A	acceptor_loss	0.9800
6:26197266:CCT:C	acceptor_loss	0.9800
6:26197268:T:G	acceptor_loss	0.9800
6:26197267:CTGCT:C	acceptor_gain	0.9700
6:26197274:A:C	acceptor_gain	0.9500
6:26197274:A:AC	acceptor_gain	0.9400
6:26197264:ACC:A	acceptor_gain	0.9300
6:26197265:CCC:C	acceptor_gain	0.9300
6:26197263:AACC:A	acceptor_gain	0.9200
6:26197082:T:TA	donor_gain	0.9100
6:26197278:C:CT	acceptor_gain	0.8700
6:26197269:G:C	acceptor_loss	0.8400
6:26197262:AAACC:A	acceptor_gain	0.8100
6:26197279:G:T	acceptor_gain	0.8100
6:26197028:T:TA	donor_gain	0.8000
6:26197033:CGGA:C	donor_gain	0.7900
6:26197018:T:TA	donor_gain	0.7700
6:26197032:A:AC	donor_gain	0.6700
6:26197033:C:CC	donor_gain	0.6700
6:26197027:AT:A	donor_gain	0.6400
6:26197109:C:CT	donor_gain	0.6400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000210523 (6:26197464 C>T), RS1000309773 (6:26196951 G>A), RS1001285373 (6:26200351 A>C), RS1001612008 (6:26200208 T>A,C), RS1002049037 (6:26197865 T>G), RS1003050974 (6:26198736 G>A), RS1005162636 (6:26198723 A>G), RS1005390392 (6:26196660 C>A,T), RS1006103571 (6:26199335 G>A), RS1006575333 (6:26199288 A>G), RS1006615419 (6:26197561 ATTT>A,ATT,ATTTT), RS1006963099 (6:26196516 G>C,T), RS1007618592 (6:26196608 G>A,C,T), RS1008584696 (6:26201035 G>A), RS1008740455 (6:26198676 G>C)

Disease associations

OMIM: gene MIM:602811 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST004521_113	Autism spectrum disorder or schizophrenia	3.000000e-19
GCST004521_142	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_169	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_69	Autism spectrum disorder or schizophrenia	8.000000e-24
GCST004521_83	Autism spectrum disorder or schizophrenia	1.000000e-13
GCST007201_219	Schizophrenia	2.000000e-09
GCST007294_143	Body fat distribution (trunk fat ratio)	5.000000e-29
GCST007294_82	Body fat distribution (trunk fat ratio)	1.000000e-48
GCST007295_120	Body fat distribution (leg fat ratio)	2.000000e-46
GCST007295_91	Body fat distribution (leg fat ratio)	1.000000e-26
GCST010141_1	Beef consumption	7.000000e-13
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
GCST010143_19	Meat-related diet	5.000000e-13
GCST010143_31	Meat-related diet	7.000000e-09
GCST010143_5	Meat-related diet	4.000000e-09
GCST010702_75	Subcortical volume (MOSTest)	3.000000e-11
GCST010703_272	Brain morphology (MOSTest)	7.000000e-16
GCST012227_894	Hip circumference adjusted for BMI	4.000000e-12
GCST90020028_936	Hip circumference adjusted for BMI	4.000000e-26

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement
EFO:0008039	BMI-adjusted hip circumference

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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects cotreatment, affects expression, decreases expression, decreases methylation, increases expression	7
(+)-JQ1 compound	increases expression	4
Cyclosporine	decreases expression, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression	2
Estradiol	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression, decreases expression	2
Aflatoxin B1	affects expression, decreases methylation, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
alpha phellandrene	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
propionaldehyde	decreases expression	1
benzo(b)fluoranthene	affects expression, affects cotreatment	1
bisphenol A	increases expression, affects cotreatment	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
resorcinol	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
deguelin	increases expression	1
fenpyroximate	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
pyrimidifen	increases expression	1
thifluzamide	increases expression	1
abrine	increases expression	1
pyrachlostrobin	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1

Clinical trials (associated diseases)

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