H3C14

Summary

H3C14 (H3 clustered histone 14, HGNC:20503) is a protein-coding gene on chromosome 1q21.2, encoding Histone H3.2 (Q71DI3). Core component of nucleosome.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. This structure consists of approximately 146 bp of DNA wrapped around a nucleosome, an octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin 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; instead, they contain a palindromic termination element. This gene is found in a histone cluster on chromosome 1. This gene is one of four histone genes in the cluster that are duplicated; this record represents the telomeric copy.

Source: NCBI Gene 126961 — RefSeq curated summary.

At a glance

• Druggable target: yes
• MANE Select transcript: NM_021059

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20503
Approved symbol	H3C14
Name	H3 clustered histone 14
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC9629, H3/m, H3, H3.2, H3/M
Ensembl gene	ENSG00000203811
Ensembl biotype	protein_coding
OMIM	142780
Entrez	126961

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369158

RefSeq mRNA: 1 — MANE Select: NM_021059 NM_021059

CCDS: CCDS30848

Canonical transcript exons

ENST00000369158 — 1 exons

Exon	Start	End
ENSE00001641953	149840687	149841208

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 85.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 186.5469 / max 4482.9156, expressed in 1549 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5034	186.5469	1549

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	85.87	gold quality
adrenal tissue	UBERON:0018303	74.33	gold quality
colonic epithelium	UBERON:0000397	73.36	gold quality
cortical plate	UBERON:0005343	73.30	gold quality
bone marrow	UBERON:0002371	73.19	gold quality
ganglionic eminence	UBERON:0004023	69.50	gold quality
ventricular zone	UBERON:0003053	66.50	gold quality
right uterine tube	UBERON:0001302	66.00	gold quality
cerebellum	UBERON:0002037	63.18	gold quality
cerebellar cortex	UBERON:0002129	62.83	gold quality
cerebellar hemisphere	UBERON:0002245	62.65	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.38	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.74	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	58.69	gold quality
tonsil	UBERON:0002372	58.51	gold quality
prefrontal cortex	UBERON:0000451	57.88	gold quality
blood	UBERON:0000178	57.36	gold quality
superior frontal gyrus	UBERON:0002661	57.04	gold quality
islet of Langerhans	UBERON:0000006	56.90	gold quality
stromal cell of endometrium	CL:0002255	56.45	gold quality
prostate gland	UBERON:0002367	54.13	gold quality
granulocyte	CL:0000094	53.84	gold quality
primary visual cortex	UBERON:0002436	53.82	gold quality
mucosa of transverse colon	UBERON:0004991	53.53	gold quality
frontal cortex	UBERON:0001870	53.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	53.16	gold quality
skeletal muscle tissue	UBERON:0001134	52.93	gold quality
liver	UBERON:0002107	52.56	gold quality
duodenum	UBERON:0002114	51.65	gold quality
cerebral cortex	UBERON:0000956	51.61	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	143.05
E-ANND-3	no	1.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, TFAP2A, YY1

Literature-anchored findings (GeneRIF, showing 27)

• peptidylarginine deiminase 4 regulates histone Arg methylation by converting methyl-Arg to citrulline and releasing methylamine; data suggest that PAD4 mediates gene expression by regulating Arg methylation and citrullination in histones (PMID:15345777)
• purification of a novel JmjC domain-containing protein, JHDM1 (JmjC domain-containing histone demethylase 1), that specifically demethylates histone H3 at lysine 36 (PMID:16362057)
• BirA ligase biotinylates K4, K9, K18 and K23 in histone H3. (PMID:18452652)
• Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. (PMID:19041150)
• phosphorylation of H3T45 (H3T45ph) increases dramatically in apoptotic cells, around the time of DNA nicking (PMID:19363025)
• The acetylation of lysine(56) residue of Histone H3 is critical for genomic stability and DNA damage response. (PMID:19411844)
• Acetylation of H3 K56 does not directly affect the compaction of chromatin and has modest effects on chromatin remodeling. However, H3 K56 acetylation increases DNA breathing 7-fold. (PMID:19818718)
• UHRF1 PHD finger (including the preceding zinc-Cys4 knuckle) acts together with the adjacent double Tudor domain to specifically recognize the H3K9me3 mark. (PMID:22100450)
• NASP balances the activity of the heat shock proteins Hsc70 and Hsp90 to direct H3-H4 for degradation by chaperone-mediated autophagy (PMID:22195965)
• Here the authors report that H3R2 is also symmetrically dimethylated (H3R2me2s) by PRMT5 and PRMT7 and present in euchromatic regions. (PMID:22231400)
• H3T80ph, protruding from the nucleosome surface, promotes interactions between adjacent nucleosomes to promote chromatin compaction during mitosis in metazoan cells. (PMID:24275038)
• In vitro clipping assays confirmed the ability of both Neisseria meningitidis proteins, App and MspA, to proteolytically cleave the core histone H3. (PMID:25600171)
• Locally generated fumarate inhibits KDM2B histone demethylase activity, resulting in enhanced dimethylation of histone H3 Lys 36. (PMID:26237645)
• Results showed that high levels of MMSET in the myeloma-like cells drove the formation of hypermethyled proteoforms containing H3K36me2 co-existent with the repressive marks H3K9me2/3 and H3K27me2/3. (PMID:26272979)
• Study shows proteolytic processing of H2B and H3 in hepatocytes where four different clipping sites were localized in H3 and one in H2B. Also, clipped H3 carry distinct co-existing post-translational modifications but different from those in intact H3. (PMID:26424599)
• Results identified histone H3K27me3 as elevated in aggressive melanoma cells relative to less aggressive melanoma cells in cell culture and in patient tissues. (PMID:26621846)
• This study presented the H3 K27M mutations in posterior fossa ependymomas. (PMID:27539613)
• Study identified phosphorylation of histone H3 at serine 10 (H3S10ph) as a histone post-translational modifications with most consistent and significant difference between gastric cancer (GC) tumor and negative resection margin. H3S10 phosphorylation in GC is mediated by MSK1 through the p38- MAPK pathway. (PMID:27588146)
• Finally, mutations of H3G34 or H3P38 alleviate the inhibitory effects of H3K36M on H3K36 methylation, demonstrating that the stable interaction of H3K36M with SETD2 is critical for its inhibitory effects. (PMID:28256625)
• Findings point to epigenetic mark H3K27me3 as an important event in prostate carcinogenesis and progression. (PMID:28403887)
• Studies presented here confirm that the adenovirus 2 large E1A protein activation domain interacts with p300, as reported previously (P. Pelka, J. N. G. Ablack, J. Torchia, A. S. Turnell, R. J. A. Grand, J. S. Mymryk, Nucleic Acids Res 37:1095-1106, 2009), and that the resulting acetylation of H3K18/27 affects varied steps in transcription at different viral promoters. (PMID:29976669)
• Elevated histone H3 citrullination is associated with increased Beclin1 expression in HBV-related hepatocellular carcinoma. (PMID:31900950)
• Insulin-Like Growth Factor Binding Protein-3 Binds to Histone 3. (PMID:33401705)
• Tumor-specific overexpression of histone gene, H3C14 in gastric cancer is mediated through EGFR-FOXC1 axis. (PMID:33727172)
• Combinatorial Histone H3 Modifications Are Dynamically Altered in Distinct Cell Cycle Phases. (PMID:33818074)
• PPARgamma-Induced Global H3K27 Acetylation Maintains Osteo/Cementogenic Abilities of Periodontal Ligament Fibroblasts. (PMID:34445348)
• Is H3 K27M mutation testing relevant in the diagnostic routine of WHO grade 4 gliomas exclusively located in the corpus callosum in adults? (PMID:34800209)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:dkey-23a13.4	ENSDARG00000103819
mus_musculus	H3c13	ENSMUSG00000074403
rattus_norvegicus	H2bc18	ENSRNOG00000070591
drosophila_melanogaster	His3:CG33851	FBGN0053851
drosophila_melanogaster	His3:CG33863	FBGN0053863

Paralogs (20): CENPA (ENSG00000115163), H3-3B (ENSG00000132475), H3-3A (ENSG00000163041), H3-4 (ENSG00000168148), H3C13 (ENSG00000183598), H3-5 (ENSG00000188375), H3C12 (ENSG00000197153), H3C4 (ENSG00000197409), 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 H3.2 — Q71DI3 (reviewed: Q71DI3)

Alternative names: H3-clustered histone 13, H3-clustered histone 14, H3-clustered histone 15, Histone H3/m, Histone H3/o

All UniProt accessions (1): Q71DI3

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. During nucleosome assembly the chaperone ASF1A interacts with the histone H3-H4 heterodimer (via C-terminus of H3); this interaction is direct. Interacts with DNAJC9, CHAF1A and CHAF1B. 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 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.

Similarity. Belongs to the histone H3 family.

RefSeq proteins (1): NP_066403* (*=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 (141 total): modified residue 120, strand 5, helix 4, cross-link 3, lipid moiety-binding region 2, sequence variant 2, initiator methionine 1, chain 1, mutagenesis site 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

153 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2X4W	X-RAY DIFFRACTION	1.5
3MO8	X-RAY DIFFRACTION	1.69
4MZG	X-RAY DIFFRACTION	1.7
2X4Y	X-RAY DIFFRACTION	1.7
2X4X	X-RAY DIFFRACTION	1.85
4OUC	X-RAY DIFFRACTION	1.9
5VAC	X-RAY DIFFRACTION	1.95
6ACE	X-RAY DIFFRACTION	1.98
7UVA	X-RAY DIFFRACTION	1.98
5B0Z	X-RAY DIFFRACTION	1.99
3R93	X-RAY DIFFRACTION	2.06
4MZF	X-RAY DIFFRACTION	2.1
4MZH	X-RAY DIFFRACTION	2.2
5CIU	X-RAY DIFFRACTION	2.24
8JLB	ELECTRON MICROSCOPY	2.36
3DB3	X-RAY DIFFRACTION	2.4
8JLD	ELECTRON MICROSCOPY	2.48
3QO2	X-RAY DIFFRACTION	2.49
10YE	ELECTRON MICROSCOPY	2.5
3AV1	X-RAY DIFFRACTION	2.5
9D3P	ELECTRON MICROSCOPY	2.5
5B0Y	X-RAY DIFFRACTION	2.56
7XCR	ELECTRON MICROSCOPY	2.57
9Y46	ELECTRON MICROSCOPY	2.59
10XZ	ELECTRON MICROSCOPY	2.6
10YA	ELECTRON MICROSCOPY	2.7
10YC	ELECTRON MICROSCOPY	2.7
9D3K	ELECTRON MICROSCOPY	2.7
7XCT	ELECTRON MICROSCOPY	2.72
9Y47	ELECTRON MICROSCOPY	2.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q71DI3-F1	86.93	0.71

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 (125): 5, 80, 80, 80, 80, 80, 80, 80, 80, 80, 80, 5, 81, 87, 108, 116, 116, 123, 123, 123 …

Mutagenesis-validated functional residues (1):

Position	Phenotype
111	abolishes s-palmitoylation.

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: 177 (showing top): REACTOME_MEIOTIC_RECOMBINATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, AFFAR_YY1_TARGETS_DN, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, CUI_TCF21_TARGETS_2_DN, BURTON_ADIPOGENESIS_5, GOBP_CHROMATIN_REMODELING

GO Biological Process (4): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), gene expression (GO:0010467)

GO Molecular Function (5): DNA binding (GO:0003677), chromatin binding (GO:0003682), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (7): nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), extracellular exosome (GO:0070062), chromatin (GO:0000785), 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
binding	2
chromatin	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
macromolecule biosynthetic process	1
nucleic acid binding	1
structural molecule activity	1
protein dimerization activity	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
extracellular vesicle	1
chromosome	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

8792 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H3C14	H4C16	P02304	998
H3C14	H2AC20	Q16777	998
H3C14	H2AC19	P20670	998
H3C14	H2BC21	Q16778	998
H3C14	H4C7	Q99525	998
H3C14	WDR5	P61964	997
H3C14	CBX5	P45973	995
H3C14	DNMT3L	Q9UJW3	994
H3C14	CBX3	Q13185	991
H3C14	BRD4	O60885	989
H3C14	DNMT3A	Q9Y6K1	987
H3C14	RAG2	P55895	977
H3C14	CBX1	P23197	973
H3C14	DNMT1	P26358	973
H3C14	HDAC1	Q13547	966

IntAct

218 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
SUZ12	EED	psi-mi:“MI:0914”(association)	0.910
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
MCM2	H4C16	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
H3C13	H4C16	psi-mi:“MI:0407”(direct interaction)	0.700
H4C16	H3C13	psi-mi:“MI:0915”(physical association)	0.700
ATXN7L3	USP27X	psi-mi:“MI:0914”(association)	0.640
NCBP1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NASP	H3C13	psi-mi:“MI:0915”(physical association)	0.600
PARP3	H3C13	psi-mi:“MI:0915”(physical association)	0.590
H3C13	MCM2	psi-mi:“MI:0915”(physical association)	0.580
DAXX	H3C13	psi-mi:“MI:0915”(physical association)	0.560
H2BC21	H3C13	psi-mi:“MI:0915”(physical association)	0.560
H3C13	DBH	psi-mi:“MI:0915”(physical association)	0.560
H3C13		psi-mi:“MI:0915”(physical association)	0.560
H3C13	GFAP	psi-mi:“MI:0915”(physical association)	0.560
H3C13	NDUFV2	psi-mi:“MI:0915”(physical association)	0.560
NOS3	H3C13	psi-mi:“MI:0915”(physical association)	0.560
OPTN	H3C13	psi-mi:“MI:0915”(physical association)	0.560
H3C13	ATXN10	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (554): HIST2H3A (Affinity Capture-MS), HIST2H3C (Affinity Capture-MS), HIST2H3D (Affinity Capture-MS), HIST2H3A (Affinity Capture-MS), HIST2H3C (Affinity Capture-MS), HIST2H3D (Affinity Capture-MS), HIST2H3C (Two-hybrid), HIST2H3A (Affinity Capture-MS), HIST2H3A (Affinity Capture-MS), HIST2H3A (Affinity Capture-MS), HIST2H3A (Affinity Capture-MS), HIST2H3A (Affinity Capture-MS), HIST2H3C (Affinity Capture-MS), HIST2H3D (Affinity Capture-MS), HIST2H3C (Affinity Capture-MS)

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

13 interactions.

A	Effect	B	Mechanism
SLBP	“up-regulates quantity by expression”	H3C15	“translation regulation”
BAZ2B	“down-regulates activity”	H3C15	binding
Sin3B_complex	“down-regulates activity”	H3C15	binding
KAT2A	“down-regulates activity”	H3C15	acetylation
KAT2B	“down-regulates activity”	H3C15	acetylation
“SAGA complex”	“down-regulates activity”	H3C15	acetylation
KDM3A	“up-regulates activity”	H3C15	demethylation
SIRT7	“up-regulates activity”	H3C15	deacetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 156 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)	8	51.2×	1e-11
Packaging Of Telomere Ends	13	27.2×	3e-14
Replacement of protamines by nucleosomes in the male pronucleus	10	25.9×	4e-11
Recognition and association of DNA glycosylase with site containing an affected purine	13	25.2×	6e-14
Cleavage of the damaged purine	13	25.2×	6e-14
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	14	24.6×	1e-14
Cleavage of the damaged pyrimidine	14	24.6×	1e-14
RNA Polymerase I Promoter Opening	14	24.6×	1e-14

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of DNA recombination	6	49.2×	3e-07
chromosome condensation	7	43.0×	5e-08
nucleosome assembly	24	24.6×	5e-24
heterochromatin formation	12	22.4×	9e-11
chromatin organization	12	8.7×	2e-06
DNA repair	10	4.7×	6e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

54 predictions. Top by Δscore:

Variant	Effect	Δscore
1:149840921:AAAGT:A	donor_gain	0.6000
1:149840727:T:TA	donor_gain	0.5900
1:149840717:CGATG:C	donor_gain	0.4600
1:149840718:GATGG:G	donor_gain	0.4600
1:149840719:ATGGA:A	donor_gain	0.4600
1:149840874:T:TA	donor_gain	0.4600
1:149840989:T:TA	donor_gain	0.4500
1:149840745:T:TA	donor_gain	0.4100
1:149840944:CCAG:C	donor_gain	0.4100
1:149840705:G:GA	donor_gain	0.3900
1:149840860:AGG:A	donor_gain	0.3900
1:149840749:AAG:A	donor_gain	0.3700
1:149840925:T:TA	donor_gain	0.3500
1:149840943:A:AC	donor_gain	0.3500
1:149840944:C:CC	donor_gain	0.3500
1:149840943:ACCAG:A	donor_gain	0.3300
1:149840944:CCAGC:C	donor_gain	0.3300
1:149840787:T:TA	donor_gain	0.3200
1:149840939:GCGTA:G	donor_loss	0.3100
1:149840940:CGTA:C	donor_loss	0.3100
1:149840941:GTA:G	donor_loss	0.3100
1:149840942:TACCA:T	donor_loss	0.3100
1:149840943:ACC:A	donor_loss	0.3100
1:149840944:CCA:C	donor_loss	0.3100
1:149840871:G:A	donor_gain	0.3000
1:149840849:C:CA	donor_gain	0.2900
1:149840847:AGC:A	donor_gain	0.2800
1:149840938:CGCG:C	donor_loss	0.2800
1:149840945:C:G	donor_loss	0.2800
1:149840966:G:A	donor_gain	0.2800

AlphaMissense

861 scored. Top likely-pathogenic:

dbSNP variants (sampled 244 via entrez): RS1160878469 (1:149842993 G>A,C,T), RS1162499767 (1:149843151 A>G), RS1180052086 (1:149843025 T>A), RS1187806970 (1:149843166 A>G), RS1204441607 (1:149843083 C>T), RS1210770227 (1:149843100 A>C), RS1219881824 (1:149843188 C>T), RS1226957240 (1:149843117 G>A,T), RS1237972637 (1:149843074 G>A), RS1265067741 (1:149843182 G>A), RS1266503288 (1:149843093 G>A), RS1293171935 (1:149843193 A>C), RS1299265234 (1:149843207 T>C), RS1312368904 (1:149843106 A>G), RS1316313632 (1:149843131 G>A)

Disease associations

OMIM: gene MIM:142780 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295875 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
ethyl-p-hydroxybenzoate	decreases expression	1
CGP 52608	increases reaction, affects binding	1
Arsenic	increases expression, increases abundance	1
Doxorubicin	affects expression	1
Oxygen	decreases expression	1
Smoke	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118775	Binding	Binding affinity to HIST2H3A in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2R1	SEES3-1V human HIST2H3C, clone1	Embryonic stem cell	Male
CVCL_A2R2	SEES3-1V human HIST2H3C, clone2	Embryonic stem cell	Male
CVCL_A2R3	SEES3-1V human HIST2H3C, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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