H3C2

Summary

H3C2 (H3 clustered histone 2, HGNC:4776) 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. 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 the large histone gene cluster on chromosome 6p22-p21.3.

Source: NCBI Gene 8358 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 14 total
• Cancer driver (intOGen): activating (oncogene-like) across 4 cancer types
• MANE Select transcript: NM_003537

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4776
Approved symbol	H3C2
Name	H3 clustered histone 2
Location	6p22.2
Locus type	gene with protein product
Status	Approved
Aliases	H3/l
Ensembl gene	ENSG00000286522
Ensembl biotype	protein_coding
OMIM	602819
Entrez	8358

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000621411

RefSeq mRNA: 1 — MANE Select: NM_003537 NM_003537

CCDS: CCDS4573

Canonical transcript exons

ENST00000621411 — 1 exons

Exon	Start	End
ENSE00003712382	26031589	26032099

Expression profiles

Bgee: expression breadth broad, 94 present calls, max score 96.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2264.7991 / max 64512.3673, expressed in 1791 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
72298	2264.7991	1791

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	96.37	gold quality
colonic epithelium	UBERON:0000397	86.91	gold quality
bone marrow cell	CL:0002092	85.95	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.96	gold quality
bone marrow	UBERON:0002371	71.98	gold quality
ventricular zone	UBERON:0003053	65.56	gold quality
mucosa of transverse colon	UBERON:0004991	57.30	gold quality
tonsil	UBERON:0002372	55.59	gold quality
ganglionic eminence	UBERON:0004023	54.36	gold quality
monocyte	CL:0000576	54.18	gold quality
mononuclear cell	CL:0000842	54.13	gold quality
leukocyte	CL:0000738	52.49	gold quality
tendon of biceps brachii	UBERON:0008188	51.66	silver quality
embryo	UBERON:0000922	51.50	gold quality
thymus	UBERON:0002370	50.49	gold quality
blood	UBERON:0000178	49.77	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cranial nerve II	UBERON:0000941	48.66	silver quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
corpus callosum	UBERON:0002336	48.54	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
quadriceps femoris	UBERON:0001377	48.47	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	1489.26
E-MTAB-10662	yes	374.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

Literature-anchored findings (GeneRIF, showing 9)

• a catalytic and inhibitory loop mechanism may better describe the cross-talk relationship between H2B ubiquitination and H3 Lys-79 methylation (PMID:20442396)
• MSK1- and MSK2-mediated H3K27me3S28 phosphorylation serves as a mechanism to activate a subset of PcG target genes determined by the biological stimuli and thereby modulate the gene expression program determining cell fate. (PMID:20864036)
• These findings suggested that at metaphase Thr 3 phosphorylated histone H3 may also participate in kinetochore assembly to promote faithful chromosome segregation and serve as another recognition code for kinetochore proteins. (PMID:20920473)
• These data suggest that adult brainstem gliomas differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) mutations are frequent in adult brainstem gliomas. (PMID:24242757)
• Study examined the relationship of K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A) with specific pontine glioma biology (PMID:26399631)
• This study showed that HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all Diffuse intrinsic pontine glioma. (PMID:26727948)
• H3K27M mutation in H3F3A occurs exclusively in pediatric high-grade gliomas arising from the midline and presents with varied histomorphological features ranging from low-grade pilomyxoid astrocytoma to highly pleomorphic glioblastoma along (PMID:29063957)
• Histone H3K27M Mutation Overrides Histological Grading in Pediatric Gliomas. (PMID:32433577)
• Molecular assessment of paratesticular rhabdomyomas demonstrates recurrent findings, including a novel H3C2 p.K37I mutation. (PMID:35842480)

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), H3C11 (ENSG00000275379), H3C1 (ENSG00000275714), H3C7 (ENSG00000277775), H3C10 (ENSG00000278828), 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_003528* (*=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: 171 (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, FISCHER_G1_S_CELL_CYCLE, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_TELOMERE_ORGANIZATION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, FISCHER_DREAM_TARGETS, TURASHVILI_BREAST_CARCINOMA_DUCTAL_VS_LOBULAR_UP, GOBP_PROTEIN_DNA_COMPLEX_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

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 4 cancer types — BLCA, BRCA, DLBCLNOS, ESCA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	10
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

83 predictions. Top by Δscore:

Variant	Effect	Δscore
6:26031868:T:TA	donor_gain	0.7100
6:26031653:CG:C	donor_gain	0.6800
6:26031653:CGCT:C	donor_gain	0.6700
6:26031652:A:AC	donor_gain	0.5700
6:26031653:C:CC	donor_gain	0.5700
6:26031842:T:TA	donor_gain	0.5000
6:26032021:C:CT	donor_gain	0.5000
6:26031770:ACAAG:A	donor_gain	0.4800
6:26031771:CAAGC:C	donor_gain	0.4800
6:26031787:CCA:C	donor_gain	0.4700
6:26031788:CA:C	donor_gain	0.4700
6:26031849:A:T	donor_gain	0.4700
6:26031763:AGGC:A	donor_gain	0.4600
6:26031794:C:CT	donor_gain	0.4500
6:26031844:G:T	donor_gain	0.4500
6:26031845:C:T	donor_gain	0.4400
6:26031774:G:A	donor_gain	0.4300
6:26031843:CGC:C	donor_gain	0.4200
6:26031795:G:T	donor_gain	0.4000
6:26032015:CT:C	donor_gain	0.4000
6:26032016:TT:T	donor_gain	0.4000
6:26032017:TT:T	donor_gain	0.4000
6:26031790:TC:T	donor_gain	0.3900
6:26031791:C:T	donor_gain	0.3900
6:26031848:C:CT	donor_gain	0.3900
6:26031801:CT:C	acceptor_gain	0.3800
6:26032013:CGCT:C	donor_gain	0.3800
6:26031766:C:CA	donor_gain	0.3700
6:26031810:C:A	acceptor_gain	0.3700
6:26031771:CAAG:C	donor_gain	0.3600

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000820399 (6:26033566 C>T), RS1002441844 (6:26033590 A>C,G,T), RS1003712563 (6:26032541 G>C), RS1004562472 (6:26031631 T>A,C,G), RS1004834258 (6:26031495 C>T), RS1005568292 (6:26032517 T>C), RS1005829550 (6:26032244 C>G,T), RS1006245094 (6:26031348 C>A,T), RS1006839948 (6:26033345 T>C,G), RS1006915413 (6:26033207 G>A,C), RS1007049669 (6:26032981 T>A), RS1007840826 (6:26034014 C>A,T), RS1008415274 (6:26031465 A>G), RS1008542040 (6:26031098 A>G), RS1008559427 (6:26031185 G>A)

Disease associations

OMIM: gene MIM:602819 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): squamous cell lung carcinoma (MONDO:0005097)

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST004521_113	Autism spectrum disorder or schizophrenia	3.000000e-19
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
GCST006945_12	Feeling guilty	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

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009595	guilt measurement
EFO:0008111	diet measurement
EFO:0004346	neuroimaging measurement

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

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation, affects expression	3
sodium arsenite	decreases expression	2
Benzo(a)pyrene	decreases expression	2
Tetrachlorodibenzodioxin	increases expression, affects expression, affects cotreatment	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
afuresertib	decreases expression	1
sotorasib	increases expression, affects cotreatment	1
methylmercuric chloride	increases expression	1
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
thallium sulfate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ferrous chloride	increases expression	1
nickel sulfate	increases expression	1
resorcinol	decreases expression	1
hydroquinone	decreases expression	1
brequinar	decreases expression	1
deguelin	increases expression	1
2-palmitoylglycerol	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
jinfukang	decreases expression, affects cotreatment	1
incobotulinumtoxinA	decreases expression	1
trametinib	affects cotreatment, increases expression	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C1MX	SU-DIPG-XXI	Cancer cell line	Male
CVCL_C1N4	SU-DIPG-XXXIII	Cancer cell line
CVCL_C1N5	SU-DIPG-XXXVI	Cancer cell line
CVCL_C1N6	SU-DIPG-XXXVIII	Cancer cell line
CVCL_C1NI	SJ-DIPGX9c	Cancer cell line	Female
CVCL_IT39	SU-DIPG-IV	Cancer cell line	Female
CVCL_IT44	VUMC-DIPG-B	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03725423	PHASE4	UNKNOWN	Apatinib for Advanced Lung Squmamous Carcinoma
NCT04132102	PHASE4	UNKNOWN	To Evaluate the Efficacy of Afatinib in Advanced Lung Squamous Cell Carcinoma With EGFR Sensitive Mutation
NCT05782764	PHASE4	UNKNOWN	A Study of Endostar Combined With Chemotherapy and Immunotherapy in Lung Squamous Cell Carcinom
NCT07567313	PHASE4	NOT_YET_RECRUITING	Stage IV Lung Squamous Cell Carcinoma Treated With or Without Bronchial Artery Chemoembolization After First-line Chemotherapy and Immunotherapy
NCT00002852	PHASE3	COMPLETED	Surgery With or Without Chemotherapy in Treating Patients With Stage I Non-small Cell Lung Cancer
NCT00005838	PHASE3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy With or Without AE-941 in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00020709	PHASE3	COMPLETED	Combination Chemotherapy and Radiation Therapy With or Without Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery
NCT00049543	PHASE3	COMPLETED	Gefitinib in Treating Patients With Stage IB, II, or IIIA Non-small Cell Lung Cancer That Was Completely Removed by Surgery
NCT00946712	PHASE3	TERMINATED	S0819: Carboplatin and Paclitaxel With or Without Bevacizumab and/or Cetuximab in Treating Patients With Stage IV or Recurrent Non-Small Cell Lung Cancer
NCT01082549	PHASE3	COMPLETED	Trial of Gemcitabine/Carboplatin With or Without Iniparib (SAR240550) (a PARP1 Inhibitor) in Subjects With Previously Untreated Stage IV Squamous Non-Small-Cell Lung Cancer (NSCLC)
NCT01947062	PHASE3	UNKNOWN	Metronomic Cyclophosphamide in Combination With Standard Chemotherapy for Squamous Cell Lung Carcinoma
NCT02785952	PHASE3	ACTIVE_NOT_RECRUITING	Lung-MAP: Nivolumab With or Without Ipilimumab as Second-Line Therapy in Treating Patients With Recurrent Stage IV Squamous Cell Lung Cancer and No Matching Biomarkers
NCT03866993	PHASE3	COMPLETED	A Study of Anti-PD-1 AK105 in Patients With Metastatic Squamous Non-small Cell Lung Cancer
NCT05943795	PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
NCT00040794	PHASE2	COMPLETED	Combination Chemotherapy, Radiation Therapy, and Gefitinib in Treating Patients With Stage III Non-Small Cell Lung Cancer
NCT00087412	PHASE2	COMPLETED	S0341: Erlotinib in Treating Patients With Advanced Primary Non-Small Cell Lung Cancer
NCT00118183	PHASE2	COMPLETED	Docetaxel With Either Cetuximab or Bortezomib as First-Line Therapy in Treating Patients With Stage III or Stage IV Non-Small Cell Lung Cancer
NCT00334815	PHASE2	ACTIVE_NOT_RECRUITING	Combination Chemotherapy, Radiation Therapy, and Bevacizumab in Treating Patients With Newly Diagnosed Stage III Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
NCT00368992	PHASE2	COMPLETED	S0536: Cetuximab, Paclitaxel, Carboplatin, and Bevacizumab in Treating Patients With Advanced Non-Small Cell Lung Cancer
NCT00387374	PHASE2	COMPLETED	Radiation Therapy, Bevacizumab, Paclitaxel, and Carboplatin in Treating Patients With Unresectable Stage IIIB or Stage IV Non-Small Cell Lung Cancer at High Risk for Hemoptysis Caused by Bevacizumab
NCT01294306	PHASE2	COMPLETED	MK2206 and Erlotinib Hydrochloride in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response to Erlotinib Hydrochloride Therapy
NCT01491633	PHASE2	TERMINATED	Dasatinib in Advanced Squamous Cell Lung Cancer
NCT01557959	PHASE2	COMPLETED	Docetaxel, Cisplatin, Pegfilgrastim, and Erlotinib Hydrochloride in Treating Patients With Stage IIIB or Stage IV Non-Small Cell Lung Cancer
NCT01660399	PHASE2	UNKNOWN	Clinical Trial of Boanmycin Hydrochloride With Docetaxel for Patients With Lung Squamous Cell Cancer as Chemotherapy
NCT01795768	PHASE2	UNKNOWN	Proof-of-Concept Study of AZD4547 in Patients With FGFR1 or FGFR2 Amplified Tumours
NCT01807546	PHASE2	COMPLETED	Oral Rigosertib for Squamous Cell Carcinoma
NCT01948141	PHASE2	COMPLETED	Nintedanib in Treating Patients With Advanced Non-Small Cell Lung Cancer Who Have Failed Up to Two Previous Chemotherapy Regimens
NCT01969955	PHASE2	UNKNOWN	Nab-paclitaxel as Second-line Therapy in Locally Advanced or Metastatic Squamous Lung Cancer
NCT02009605	PHASE2	UNKNOWN	Icotinib in Previously Treated Non/Light-smoking Patients With Advanced Squamous Cell Lung Cancer
NCT02186847	PHASE2	COMPLETED	Chemotherapy and Radiation Therapy With or Without Metformin Hydrochloride in Treating Patients With Stage III Non-small Cell Lung Cancer
NCT02264210	PHASE2	COMPLETED	Icotinib for Completed Resected IB NSCLC With EGFR Mutation
NCT02417701	PHASE2	COMPLETED	Sapanisertib in Treating Patients With Stage IV or Recurrent Lung Cancer
NCT02423590	PHASE2	UNKNOWN	Study of Gemcitabine/Carboplatin First-line Chemotherapy +/- Apatorsen in Advanced Squamous Cell Lung Cancers
NCT02785913	PHASE2	COMPLETED	Lung-MAP: Taselisib as Therapy in Treating Patients With Stage IV Squamous Cell Lung Cancer and Positive Biomarker Matches
NCT02787473	PHASE2	UNKNOWN	A Study of Pemetrexed Plus Cisplatin With Concurrent Radiation Therapy Followed by Docetaxel Consolidation in Patients With Inoperable Squamous Cell Lung Cancer
NCT02831933	PHASE2	TERMINATED	Trial of Radiation and Gene Therapy Before Nivolumab for Metastatic Non-Small Cell Lung Carcinoma and Uveal Melanoma
NCT02852083	PHASE2	UNKNOWN	A Trial With Metronomic Low-dose Treosulfan, Pioglitazone and Clarithromycin Versus Standard Treatment in NSCLC
NCT02920476	PHASE2	COMPLETED	TAS-102 in Previously Treated Unresectable or Metastatic Squamous Cell Lung Carcinoma (UF-STO-LUNG-003)
NCT03041181	PHASE2	TERMINATED	Single Agent Chemotherapy +/- Nivolumab in Patients With Advanced Squamous or Non-squamous NSCLC With Primary Resistance to Prior PD-1 or PDL-1 Inhibitor
NCT03373760	PHASE2	COMPLETED	Durvalumab and Tremelimumab in Treating Patients With Recurrent Stage IV Lung Cancer