H4C16

Summary

H4C16 (H4 histone 16, HGNC:20510) is a protein-coding gene on chromosome 12p12.3, encoding Histone H4 (P62805). Core component of nucleosome.

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone 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 H4 family. Transcripts from this gene lack polyA tails; instead, they contain a palindromic termination element.

Source: NCBI Gene 121504 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 13 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_175054

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20510
Approved symbol	H4C16
Name	H4 histone 16
Location	12p12.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC24116
Ensembl gene	ENSG00000197837
Ensembl biotype	protein_coding
OMIM	615069
Entrez	121504

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 protein_coding

ENST00000358064, ENST00000537096, ENST00000537853, ENST00000539745, ENST00000540565, ENST00000541592

RefSeq mRNA: 1 — MANE Select: NM_175054 NM_175054

CCDS: CCDS8665

Canonical transcript exons

ENST00000539745 — 1 exons

Exon	Start	End
ENSE00002309071	14770720	14771131

Expression profiles

Bgee: expression breadth ubiquitous, 133 present calls, max score 94.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 94.9663 / max 1632.9013, expressed in 1754 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
129847	94.8664	1754
206633	0.0998	39

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	94.15	gold quality
adrenal tissue	UBERON:0018303	88.93	gold quality
calcaneal tendon	UBERON:0003701	86.91	gold quality
colonic epithelium	UBERON:0000397	86.42	gold quality
tonsil	UBERON:0002372	85.80	gold quality
right uterine tube	UBERON:0001302	81.62	gold quality
bone marrow	UBERON:0002371	81.37	gold quality
prostate gland	UBERON:0002367	78.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.31	silver quality
sural nerve	UBERON:0015488	77.97	gold quality
body of pancreas	UBERON:0001150	76.89	gold quality
lower esophagus mucosa	UBERON:0035834	76.77	gold quality
stomach	UBERON:0000945	76.62	gold quality
uterine cervix	UBERON:0000002	76.07	gold quality
pancreas	UBERON:0001264	75.91	gold quality
vermiform appendix	UBERON:0001154	75.63	gold quality
left ovary	UBERON:0002119	75.50	gold quality
ovary	UBERON:0000992	75.24	gold quality
esophagus mucosa	UBERON:0002469	75.24	gold quality
saliva-secreting gland	UBERON:0001044	75.16	gold quality
urinary bladder	UBERON:0001255	75.13	gold quality
vagina	UBERON:0000996	75.12	gold quality
lymph node	UBERON:0000029	74.80	gold quality
minor salivary gland	UBERON:0001830	74.74	gold quality
ectocervix	UBERON:0012249	74.67	gold quality
descending thoracic aorta	UBERON:0002345	74.64	gold quality
rectum	UBERON:0001052	74.60	gold quality
granulocyte	CL:0000094	74.53	gold quality
popliteal artery	UBERON:0002250	74.44	gold quality
tibial artery	UBERON:0007610	74.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.69

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• low levels of histone acetylation is associated with the development and progression of gastric carcinomas, possibly through alteration of gene expression (PMID:12385581)
• overexpression of MTA1 protein and acetylation level of histone H4 protein are closely related (PMID:15095300)
• 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)
• lack of biotinylation of K12 in histone H4 is an early signaling event in response to double-strand breaks (PMID:16177192)
• The decrease in trimethylation of lysine 20 of histone H4 in breast cancer cells was accompanied by diminished expression of Suv4-20h2 histone methyltransferase. (PMID:16322686)
• incorporation of acetylated histone H4-K16 into nucleosomal arrays inhibits the formation of compact 30-nanometer-like fibers and impedes the ability of chromatin to form cross-fiber interactions (PMID:16469925)
• Apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. (PMID:16531610)
• BTG2 contributes to retinoic acid activity by favoring differentiation through a gene-specific modification of histone H4 arginine methylation and acetylation levels. (PMID:16782888)
• Relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. (PMID:17522015)
• H4 tail and its acetylation have novel roles in mediating recruitment of multiple regulatory factors that can change chromatin states for transcription regulation (PMID:17548343)
• Brd2 bromodomain 2 is monomeric in solution and dynamically interacts with H4-AcK12; additional secondary elements in the long ZA loop may be a common characteristic of BET bromodomains. (PMID:17848202)
• Spermatids Hypac-H4 impairment in mixed atrophy did not deteriorate further by AZFc region deletion. (PMID:18001726)
• the SET8 and PCNA interaction couples H4-K20 methylation with DNA replication (PMID:18319261)
• H4K20 monomethylation and PR-SET7 are important for L3MBTL1 function (PMID:18408754)
• High expression of acetylated H4 is more common in aggressive than indolent cutaneous T-cell lymphoma. (PMID:18671804)
• Jade-1/1L are crucial co-factors for HBO1-mediated histone H4 acetylation (PMID:18684714)
• Our findings indicate an important role of histone H4 modifications in bronchial carcinogenesis (PMID:18974389)
• results indicate, by acetylation of histone H4 K16 during S-phase, early replicating chromatin domains acquire the H4K16ac-K20me2 epigenetic label that persists on the chromatin throughout mitosis & is deacetylated in early G1-phase of the next cell cycle (PMID:19348949)
• acetylated H4 is overexpressed in diffuse large B-cell lymphoma and peripheral T-cell lymphoma relative to normal lymphoid tissue. (PMID:19438744)
• The release of histone H4 by holocrine secretion from the sebaceous gland may play an important role in innate immunity. (PMID:19536143)
• histone modification including PRC2-mediated repressive histone marker H3K27me3 and active histone marker acH4 may involve in CD11b transcription during HL-60 leukemia cells reprogramming to terminal differentiation (PMID:19578722)
• A role of Cdk7 in regulating elongation is further suggested by enhanced histone H4 acetylation and diminished histone H4 trimethylation on lysine 36-two marks of elongation-within genes when the kinase was inhibited. (PMID:19667075)
• Downregulated by zinc and upregulated by docosahexaenoate in a neuroblastoma cell line. (PMID:19747413)
• Data showed the dynamic fluctuation of histone H4 acetylation levels during mitosis, as well as acetylation changes in response to structurally distinct histone deacetylase inhibitors. (PMID:19805290)
• Data directly implicate BBAP in the monoubiquitylation and additional posttranslational modification of histone H4 and an associated DNA damage response. (PMID:19818714)
• Our findings reveal the molecular mechanisms whereby the DNA sequences within specific gene bodies are sufficient to nucleate the monomethylation of histone H4 lysine 200 which, in turn, reduces gene expression by half. (PMID:20512922)
• the imatinib-induced hemoglobinization and erythroid differentiation in K562 cells are associated with global histone H4 (PMID:20949922)
• The crystal structure of an HJURP-CENP-A-histone H4 complex shows that HJURP binds a CENP-A-H4 heterodimer (PMID:21478274)
• phosphorylation of histone H4 Ser 47 catalyzed by the PAK2 kinase, promotes nucleosome assembly of H3.3-H4 and inhibits nucleosome assembly of H3.1-H4 by increasing the binding affinity of HIRA to H3.3-H4 and reducing association of CAF-1 with H3.1-H4 (PMID:21724829)
• TNF-alpha inhibition of AQP5 expression in human salivary gland acinar cells is due to the epigenetic mechanism by suppression of acetylation of histone H4. (PMID:21973049)
• HAT1 differentially impacts nucleosome assembly of H3.1-H4 and H3.3-H4. (PMID:22228774)
• our data suggest that global histone H3 and H4 modification patterns are potential markers of tumor recurrence and disease-free survival in non-small cell lung cancer (PMID:22360506)
• Human PIH1 domain-containing protein 1 (PIH1) interacts directly with histone H4 and recruits the Brg1-SWI/SNF complex via SNF5 to human rRNA genes. (PMID:22368283)
• This study focused on the distribution of a specific histone modification, namely H4K12ac, in human sperm and characterized its specific enrichment sites in promoters throughout the whole human genome. (PMID:22894908)
• SRP68/72 heterodimers as major nuclear proteins whose binding of histone H4 tail is inhibited by H4R3 methylation. (PMID:23048028)
• Data indicate that G1-phase histone assembly is restricted to CENP-A and H4. (PMID:23363600)
• An increase in histone H4 acetylation caused by hypoxia in human neuroblastoma cell lines corresponds to increased levels of N-myc transcription factor in these cells. (PMID:24481548)
• Acetylation at lysine 5 of histone H4 associated with lytic gene promoters during reactivation of Kaposi’s sarcoma-associated herpesvirus. (PMID:25283865)
• Sumoylated human histone H4 prevents chromatin compaction by inhibiting long-range internucleosomal interactions. (PMID:25294883)
• Systemic lupus erythematosus appears to be associated with an imbalance in histone acetyltransferases and histone deacetylase enzymes favoring pathologic H4 acetylation. (PMID:25611806)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:153409	ENSDARG00000061547
danio_rerio	si:dkey-261m9.17	ENSDARG00000111165
danio_rerio	hist1h4l	ENSDARG00000111247
danio_rerio	si:ch211-113a14.6	ENSDARG00000116781
mus_musculus	H4c11	ENSMUSG00000067455
mus_musculus	H4c2	ENSMUSG00000069266
rattus_norvegicus	H4c14	ENSRNOG00000066473

Paralogs (14): H4C8 (ENSG00000158406), H4C3 (ENSG00000197061), H4C11 (ENSG00000197238), H4C15 (ENSG00000270276), H4C14 (ENSG00000270882), H4C12 (ENSG00000273542), H4C6 (ENSG00000274618), H4C13 (ENSG00000275126), H4C7 (ENSG00000275663), H4C9 (ENSG00000276180), H4C5 (ENSG00000276966), H4C4 (ENSG00000277157), H4C1 (ENSG00000278637), H4C2 (ENSG00000278705)

Protein

Protein identifiers

Histone H4 — P62805 (reviewed: P62805)

All UniProt accessions (2): B2R4R0, P62805

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. Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers. Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct. 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 at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin. Acetylated as part of spermatogenesis progression prior to histone-to-protamine exchange. Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation. Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage. Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3). Monomethylation is performed by KMT5A/SET8. Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing. Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators. H4K20me2 and H4K20me3 are demethylated into monomethyl (H4K20me1) by RSBN1. H4K20me1, H4K20me2 and H4K20me3 are demethylated by RAD23A and RAD23B. H4K20me1 is demethylated by PHF8. Acetyl-methylated at Lys-6 and Lys-13 (H4K5acme and H4K12acme, respectively), acetyl-methylation is an epigenetic mark of active chromatin associated with increased transcriptional initiation. Acetyl-methylation is formed by acetylation by EP300/p300 of lysine residues that are already monomethylated on the same side chain. H4K5acme and H4K12acme marks specifically bind BRD2. Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4. 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. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me). Ubiquitinated; by PHF7. Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage. Sumoylated, which is associated with transcriptional 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. Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes. Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription. Delactylated by SIRT3 at Lys-17 (H4K16la).

Disease relevance. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 1 (TEBIVANED1) [MIM:619758] An autosomal dominant disorder with onset in infancy, characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, poor or absent speech, and characteristic dysmorphic facial features, including hypertelorism and abnormal nose. Other variable neurologic and systemic features may also occur. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED1 is caused by variants in H4C3. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 2 (TEBIVANED2) [MIM:619759] An autosomal dominant disorder characterized by poor overall growth, microcephaly, hypotonia, profound global developmental delay, impaired intellectual development, absent speech, and characteristic dysmorphic facial features, including hypertelorism, abnormal nose, and wide mouth. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED2 is caused by variants in H4C11. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 3 (TEBIVANED3) [MIM:619950] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, impaired intellectual development, and speech difficulties. More variable features include hypotonia, microcephaly, and dysmorphic facies. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED3 is caused by variants in H4C5. Tessadori-Bicknell-Van Haaften neurodevelopmental syndrome 4 (TEBIVANED4) [MIM:619951] An autosomal dominant disorder characterized by global developmental delay with poor overall growth, variably impaired intellectual development, learning difficulties, distal skeletal anomalies, and dysmorphic facies. Some patients have visual or hearing deficits. The disease is caused by variants affecting the gene represented in this entry. TEBIVANED4 is caused by variants in H4C9. Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.

Similarity. Belongs to the histone H4 family.

RefSeq proteins (1): NP_778224* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001951	Histone_H4	Family
IPR004823	TAF_TATA-bd_Histone-like_dom	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR019809	Histone_H4_CS	Conserved_site
IPR035425	CENP-T/H4_C	Domain

Pfam: PF15511

UniProt features (138 total): modified residue 94, sequence variant 17, cross-link 8, strand 4, helix 4, mutagenesis site 2, sequence conflict 2, turn 2, initiator methionine 1, chain 1, DNA-binding region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

626 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3F9X	X-RAY DIFFRACTION	1.25
8PEF	X-RAY DIFFRACTION	1.28
5TEG	X-RAY DIFFRACTION	1.3
3UVW	X-RAY DIFFRACTION	1.37
8UK5	X-RAY DIFFRACTION	1.4
1ZKK	X-RAY DIFFRACTION	1.45
4YY6	X-RAY DIFFRACTION	1.45
3F9Y	X-RAY DIFFRACTION	1.5
3QZT	X-RAY DIFFRACTION	1.5
4YYI	X-RAY DIFFRACTION	1.5
4YYM	X-RAY DIFFRACTION	1.5
5FFW	X-RAY DIFFRACTION	1.5
2BQZ	X-RAY DIFFRACTION	1.5
4YYD	X-RAY DIFFRACTION	1.52
8B5C	X-RAY DIFFRACTION	1.58
6RXS	X-RAY DIFFRACTION	1.6
3F9W	X-RAY DIFFRACTION	1.6
3F9Z	X-RAY DIFFRACTION	1.6
6VO5	X-RAY DIFFRACTION	1.6
7M98	X-RAY DIFFRACTION	1.6
2IG0	X-RAY DIFFRACTION	1.7
3O36	X-RAY DIFFRACTION	1.7
4QUT	X-RAY DIFFRACTION	1.7
5YE3	X-RAY DIFFRACTION	1.7
4YYH	X-RAY DIFFRACTION	1.74
8TGP	X-RAY DIFFRACTION	1.76
4YYK	X-RAY DIFFRACTION	1.79
5YE4	X-RAY DIFFRACTION	1.8
3QZS	X-RAY DIFFRACTION	1.8
4QUU	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62805-F1	90.90	0.75

Antibody-complex structures (SAbDab): 21 — 5YE3, 5YE4, 6E0C, 6E0P, 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 (102): 4, 21, 32, 32, 60, 80, 92, 92, 6, 6, 6, 6, 6, 6, 6, 6, 9, 9, 9, 9 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
13	impaired methylation by n6amt1.
32	abolished ufmylation.

Function

Pathways and Gene Ontology

Reactome pathways

60 pathways

ID	Pathway
R-HSA-110328	Recognition and association of DNA glycosylase with site containing an affected pyrimidine
R-HSA-110329	Cleavage of the damaged pyrimidine
R-HSA-110330	Recognition and association of DNA glycosylase with site containing an affected purine
R-HSA-110331	Cleavage of the damaged purine
R-HSA-1221632	Meiotic synapsis
R-HSA-171306	Packaging Of Telomere Ends
R-HSA-1912408	Pre-NOTCH Transcription and Translation
R-HSA-201722	Formation of the beta-catenin:TCF transactivating complex
R-HSA-212300	PRC2 methylates histones and DNA
R-HSA-2299718	Condensation of Prophase Chromosomes
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-2559586	DNA Damage/Telomere Stress Induced Senescence
R-HSA-3214815	HDACs deacetylate histones
R-HSA-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-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-4551638	SUMOylation of chromatin organization proteins
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-5693565	Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
R-HSA-5693571	Nonhomologous End-Joining (NHEJ)
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 205 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_MEIOTIC_SYNAPSIS, REACTOME_G2_M_DNA_DAMAGE_CHECKPOINT, GOBP_TELOMERE_ORGANIZATION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_REGULATION_OF_MEGAKARYOCYTE_DIFFERENTIATION, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME

GO Biological Process (6): chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), telomere organization (GO:0032200), negative regulation of megakaryocyte differentiation (GO:0045653), protein localization to CENP-A containing chromatin (GO:0061644), mRNA 3’-end processing by stem-loop binding and cleavage (GO:0006398)

GO Molecular Function (5): DNA binding (GO:0003677), RNA binding (GO:0003723), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, telomeric region (GO:0000781), nucleosome (GO:0000786), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), membrane (GO:0016020), protein-containing complex (GO:0032991), CENP-A containing nucleosome (GO:0043505), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Chromatin modifying enzymes	5
Cellular Senescence	3
Depyrimidination	2
Depurination	2
Meiosis	1
Telomere Maintenance	1
Pre-NOTCH Expression and Processing	1
TCF dependent signaling in response to WNT	1
Epigenetic regulation of gene expression	1
Mitotic Prophase	1
Negative epigenetic regulation of rRNA expression	1
Positive epigenetic regulation of rRNA expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
nucleic acid binding	2
chromatin	2
cellular component organization	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
chromosome organization	1
megakaryocyte differentiation	1
negative regulation of myeloid cell differentiation	1
regulation of megakaryocyte differentiation	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
histone mRNA metabolic process	1
mRNA 3’-end processing	1
structural molecule activity	1
protein dimerization activity	1
binding	1
chromosomal region	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular_component	1
nucleosome	1
CENP-A containing chromatin	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

672 interactions, top by confidence:

A	B	Type	Score
ASF1A	H4C16	psi-mi:“MI:0915”(physical association)	0.950
H4C16	ASF1A	psi-mi:“MI:0915”(physical association)	0.950
ASF1A	H4C16	psi-mi:“MI:0914”(association)	0.950
H3C1	H4C16	psi-mi:“MI:0915”(physical association)	0.890
H4C16	H3C1	psi-mi:“MI:0407”(direct interaction)	0.890
ASF1A	MCM2	psi-mi:“MI:0915”(physical association)	0.890
ASF1A	MCM2	psi-mi:“MI:0914”(association)	0.890
TP53BP1	H4C16	psi-mi:“MI:0407”(direct interaction)	0.870
H3-3A	H4C16	psi-mi:“MI:0915”(physical association)	0.860
H3-3A	H4C16	psi-mi:“MI:0914”(association)	0.860
H3-3A	H4C16	psi-mi:“MI:0407”(direct interaction)	0.860
H2AC4	H2BC11	psi-mi:“MI:0915”(physical association)	0.850

BioGRID (3544): RBBP4 (Affinity Capture-Western), HIST1H4A (Affinity Capture-Western), HIST4H4 (Biochemical Activity), HIST4H4 (Affinity Capture-MS), HIST2H4B (Affinity Capture-MS), HIST4H4 (Two-hybrid), ASF1A (Two-hybrid), HIST4H4 (Biochemical Activity), HIST4H4 (Biochemical Activity), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4I (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4E (Affinity Capture-RNA), HIST1H4A (Biochemical Activity)

ESM2 similar proteins: P02309, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62785, P62786, P62787, P62788, P62794, P62797, P62798, P62799, P62800, P62801, P62802, P62803, P62805, P62806, P62887, Q27443, Q27765, Q43083, Q4R362, Q5RCS7, Q6LAF1, Q6LAF3, Q6PMI5, Q6V9I2, Q6WV72, Q6WV73, Q6WV90, Q6WZ83, Q71V09

Diamond homologs: P02309, P04914, P04915, P08436, P09322, P0CG89, P23750, P23751, P27996, P35057, P35059, P50566, P59259, P62776, P62777, P62778, P62779, P62780, P62781, P62782, P62783, P62784, P62785, P62786, P62787, P62788, P62790, P62791, P62792, P62793, P62794, P62795, P62796, P62797, P62798, P62799, P62800, P62801, P62802, P62803

SIGNOR signaling

27 interactions.

A	Effect	B	Mechanism
TP53BP1	unknown	H4C1	binding
MAML1	“down-regulates activity”	H4C1	acetylation
“Integrator complex”	“down-regulates quantity by repression”	H4C1	“transcriptional regulation”
KAT5	“down-regulates activity”	H4C1	acetylation
H4C1	“up-regulates activity”	BRD2	relocalization
H4C1	“up-regulates activity”	BRD4	relocalization
H4C1	“up-regulates activity”	BRDT	relocalization
H4C1	“form complex”	“Nucleosome_H3.3 variant”	binding
“MSL acetyltransferase”	“down-regulates activity”	H4C1	acetylation
UFL1	“up-regulates activity”	H4C1	ubiquitination
SLBP	“up-regulates quantity by expression”	H4C1	“translation regulation”
“NSL histone acetyltransferase”	“down-regulates activity”	H4C1	acetylation
“NuA4 complex”	“down-regulates activity”	H4C1	acetylation
DTX3L	“down-regulates activity”	H4C1	monoubiquitination
“BRCA1-BARD1 complex”	“up-regulates activity”	H4C1	ubiquitination
H4C1	“form complex”	“CENP-A nucleosome”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.2 variant”	binding
H4C1	“form complex”	“Nucleosome_H2A.Z.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1 variant”	binding
H4C1	“form complex”	“Nucleosome_H3.1t variant”	binding
HAT1	“down-regulates activity”	H4C1	acetylation
H4C1	“form complex”	Nucleosome	binding
KMT5C	“down-regulates activity”	H4C1	methylation
KMT5B	“down-regulates activity”	H4C1	methylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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)	5	41.0×	2e-06
Notch-HLH transcription pathway	6	29.8×	7e-07
NOTCH1 Intracellular Domain Regulates Transcription	8	23.2×	6e-08
ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression	11	20.4×	9e-10
Constitutive Signaling by NOTCH1 PEST Domain Mutants	8	19.2×	2e-07
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	8	19.2×	2e-07
Condensation of Prophase Chromosomes	10	19.1×	6e-09
HDACs deacetylate histones	13	19.1×	9e-11

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of gene expression, epigenetic	6	25.6×	1e-05
nucleosome assembly	15	22.4×	1e-13
heterochromatin formation	8	21.7×	9e-07
epigenetic regulation of gene expression	5	20.4×	3e-04
chromatin organization	11	11.6×	9e-07
antimicrobial humoral immune response mediated by antimicrobial peptide	5	8.6×	9e-03
chromatin remodeling	11	8.5×	9e-06
DNA damage response	10	5.7×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	12
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3391852	GRCh37/hg19 12p13.2-11.1(chr12:10155706-34051988)x3	Pathogenic

SpliceAI

130 predictions. Top by Δscore:

Variant	Effect	Δscore
12:14770916:C:A	donor_gain	0.8300
12:14771108:G:C	donor_gain	0.8300
12:14770915:C:CA	donor_gain	0.8000
12:14770927:TC:T	acceptor_gain	0.7600
12:14770870:G:C	donor_gain	0.7500
12:14770929:G:C	acceptor_gain	0.7500
12:14770874:CCGCG:C	donor_gain	0.7300
12:14771107:A:AC	donor_gain	0.7300
12:14770925:CCTCG:C	acceptor_gain	0.7200
12:14770882:CGGA:C	donor_gain	0.7100
12:14771060:TGCC:T	donor_gain	0.6900
12:14770926:CTCG:C	acceptor_gain	0.6800
12:14771103:A:AC	donor_gain	0.6700
12:14771104:C:CC	donor_gain	0.6700
12:14770885:A:AC	donor_gain	0.6600
12:14770862:C:CA	donor_gain	0.6500
12:14770998:G:A	donor_gain	0.6500
12:14771062:C:CT	donor_gain	0.6500
12:14771107:AG:A	donor_gain	0.6400
12:14770924:TCCTC:T	acceptor_gain	0.6300
12:14770875:C:CT	donor_gain	0.6200
12:14770995:AATG:A	donor_gain	0.6100
12:14771063:C:CT	donor_gain	0.5800
12:14771104:CTCAG:C	donor_gain	0.5800
12:14770928:C:A	acceptor_gain	0.5700
12:14770928:C:CT	acceptor_gain	0.5700
12:14771053:AGCC:A	donor_gain	0.5200
12:14771104:CT:C	donor_gain	0.5200
12:14770929:G:GC	acceptor_gain	0.5100
12:14770828:T:TA	donor_gain	0.5000

AlphaMissense

643 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:14770782:G:C	F101L	1.000
12:14770782:G:T	F101L	1.000
12:14770784:A:G	F101L	1.000
12:14770960:C:T	G42E	1.000
12:14770961:C:A	G42W	1.000
12:14770810:T:A	K92I	0.999
12:14770813:A:G	L91P	0.999
12:14770828:T:A	D86V	0.999
12:14770829:C:G	D86H	0.999
12:14770840:A:T	V82D	0.999
12:14770849:C:G	R79P	0.999
12:14770877:C:G	A70P	0.999
12:14770899:G:C	F62L	0.999
12:14770899:G:T	F62L	0.999
12:14770901:A:G	F62L	0.999
12:14770909:A:T	L59H	0.999
12:14770931:A:G	Y52H	0.999
12:14770949:G:A	R46C	0.999
12:14770949:G:T	R46S	0.999
12:14770957:C:A	G43V	0.999
12:14770960:C:A	G42V	0.999
12:14770961:C:G	G42R	0.999
12:14770961:C:T	G42R	0.999
12:14770964:G:A	R41C	0.999
12:14770964:G:T	R41S	0.999
12:14770969:G:T	A39D	0.999
12:14770972:A:T	L38H	0.999
12:14770976:G:A	R37C	0.999
12:14770976:G:T	R37S	0.999
12:14770979:G:T	R36S	0.999

dbSNP variants (sampled 300 via entrez): RS1000511644 (12:14771126 C>T), RS1001056933 (12:14770321 C>G), RS1002467188 (12:14770580 T>C), RS1003052524 (12:14772524 C>T), RS1003348445 (12:14771235 A>G), RS1003378164 (12:14771091 A>C,G), RS1006933422 (12:14770617 C>A,T), RS1007203978 (12:14771458 T>C), RS1012469962 (12:14770785 A>C), RS1012842013 (12:14771278 T>A), RS1013861853 (12:14770352 G>A), RS1014790530 (12:14771237 A>C,T), RS1017909548 (12:14772968 G>A,T), RS1018029057 (12:14770624 C>G,T), RS1018081409 (12:14770408 G>A)

Disease associations

OMIM: gene MIM:615069 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001875_5	Pubertal anthropometrics	8.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5876 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 312 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3919831	AMREDOBRESIB	2	312

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

Binding affinities (BindingDB)

78 measured of 78 human assays (78 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-[1-[(5-fluoro-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	1 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[8-[[1-(2-methoxyethyl)piperidin-4-yl]amino]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	3 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-5-methyl-4-phenylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	4 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-[1-benzyl-2-[3-methyl-8-(methylamino)-[1,2,4]triazolo[4,3-a]pyrazin-6-yl]benzimidazol-5-yl]-4-methyl-4,5-dihydro-1H-pyridazin-6-one	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	5 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-3-methyl-N-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	7 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1,5-dimethyl-4-phenoxypyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzylbenzimidazol-2-yl)-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	8 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(4-fluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-[(3,4-difluorophenyl)methyl]benzimidazol-2-yl]-N-[1-(2-methoxyethyl)piperidin-4-yl]-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[9-benzyl-2-(4-methylpiperazin-1-yl)purin-8-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)benzimidazol-2-yl]-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3R)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-[(3S)-3-methylmorpholin-4-yl]-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	9 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-6-morpholin-4-ylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	10 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[5-(oxan-4-yl)-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	11 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-4-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	12 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methoxyacetamide	IC50	12.8 nM	US-9125915: Antitumor agent
N,3-dimethyl-6-[6-(4-methylpiperazin-1-yl)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[6-(dimethylamino)-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-3-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	13 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	14 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	15 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-N-ethyl-3-methyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[1-[(6-methyl-2-pyridinyl)methyl]-6-morpholin-4-ylimidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	17 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-methylacetamide	IC50	17.3 nM	US-9125915: Antitumor agent
6-(4-benzyl-1,5-dimethylpyrazol-3-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(3-benzylimidazo[4,5-b]pyridin-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[6-propan-2-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	18 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
methyl 2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetate	IC50	18.2 nM	US-9125915: Antitumor agent
3-methyl-6-[6-morpholin-4-yl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-[(3R)-oxolan-3-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-N-propan-2-yl-6-[1-(pyridin-2-ylmethyl)benzimidazol-2-yl]-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	20 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
2-[7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]-N-(2-hydroxyethyl)acetamide	IC50	21 nM	US-9125915: Antitumor agent
6-(1-benzylbenzimidazol-2-yl)-N,3-dimethyl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	22 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-[1-benzyl-6-(4-methylpiperazin-1-yl)imidazo[4,5-c]pyridin-2-yl]-3-methyl-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	26 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
3-methyl-6-[6-methyl-1-(pyridin-2-ylmethyl)imidazo[4,5-c]pyridin-2-yl]-N-propan-2-yl-[1,2,4]triazolo[4,3-a]pyrazin-8-amine	IC50	28 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors
6-(1-benzyl-4,5-dimethylimidazol-2-yl)-3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyrazine	IC50	31 nM	US-9266891: Substituted [1,2,4]triazolo[4,3-A]pyrazines that are BRD4 inhibitors

ChEMBL bioactivities

65 potent at pChembl≥5 of 66 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL3930178
8.52	IC50	3	nM	CHEMBL3938152
8.52	IC50	3	nM	CHEMBL3953268
8.52	IC50	3	nM	CHEMBL3916639
8.40	IC50	4	nM	CHEMBL3979803
8.40	IC50	4	nM	CHEMBL3959499
8.30	IC50	5	nM	CHEMBL3913643
8.30	IC50	5	nM	CHEMBL3939182
8.30	IC50	5	nM	CHEMBL3935504
8.15	IC50	7	nM	CHEMBL3983932
8.15	IC50	7	nM	CHEMBL3920322
8.15	IC50	7	nM	CHEMBL3923899
8.10	IC50	8	nM	CHEMBL3929450
8.10	IC50	8	nM	CHEMBL3923105
8.10	IC50	8	nM	CHEMBL3929086
8.10	IC50	8	nM	CHEMBL3927028
8.05	IC50	9	nM	CHEMBL3941148
8.05	IC50	9	nM	CHEMBL3970690
8.05	IC50	9	nM	CHEMBL3908717
8.05	IC50	9	nM	CHEMBL3951550
8.05	IC50	9	nM	AMREDOBRESIB
8.05	IC50	9	nM	CHEMBL4112988
8.05	IC50	9	nM	CHEMBL3893231
8.01	Kd	9.891	nM	CHEMBL5653589
8.01	ED50	9.891	nM	CHEMBL5653589
8.00	IC50	10	nM	CHEMBL3914807
8.00	IC50	10	nM	CHEMBL3902208
7.96	IC50	11	nM	CHEMBL3907651
7.92	IC50	12	nM	CHEMBL3973914
7.92	IC50	12	nM	CHEMBL3966649
7.89	IC50	13	nM	CHEMBL3928047
7.89	IC50	13	nM	CHEMBL3951605
7.89	IC50	13	nM	CHEMBL4114198
7.85	IC50	14	nM	CHEMBL3919702
7.85	IC50	14	nM	CHEMBL3946335
7.82	IC50	15	nM	CHEMBL3916156
7.82	IC50	15	nM	CHEMBL3937464
7.77	IC50	17	nM	CHEMBL3956797
7.77	IC50	17	nM	CHEMBL3914869
7.75	IC50	18	nM	CHEMBL3891629
7.75	IC50	18	nM	CHEMBL3947502
7.75	IC50	18	nM	CHEMBL3956941
7.70	IC50	20	nM	CHEMBL4115491
7.70	IC50	20	nM	CHEMBL3960315
7.66	IC50	22	nM	CHEMBL3946480
7.58	IC50	26	nM	CHEMBL3929241
7.55	IC50	28	nM	CHEMBL3909523
7.51	IC50	31	nM	CHEMBL3985926
7.51	IC50	31	nM	CHEMBL4107079
7.50	IC50	32	nM	CHEMBL3916033

PubChem BioAssay actives

2 with measured affinity, of 108 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	0.0099	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148510: Binding affinity to human HIST1H4A incubated for 45 mins by Kinobead based pull down assay	kd	4.0927	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects expression, affects methylation, affects binding, decreases reaction, increases reaction (+3 more)	7
Decitabine	affects binding, increases reaction, increases expression	2
Dexamethasone	increases acetylation, decreases reaction, affects binding, affects cotreatment, increases reaction	2
Progesterone	decreases reaction, increases acetylation, increases expression	2
Silicon Dioxide	increases expression, decreases expression	2
Tetrachlorodibenzodioxin	increases acetylation, affects binding, increases reaction, decreases reaction	2
Tretinoin	affects binding, increases reaction, increases acetylation	2
Valproic Acid	affects binding, increases reaction, increases acetylation	2
N-(1,3-dimethylbutyl)-N’-phenyl-p-phenylenediamine quinone	affects expression	1
terbufos	increases methylation	1
methoxyacetic acid	increases acetylation	1
beta-lapachone	increases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	decreases acetylation	1
fludarabine	affects cotreatment, increases acetylation	1
periodate-oxidized adenosine	increases acetylation, increases reaction, increases methylation, decreases reaction	1
3-deazaneplanocin	affects acetylation, affects cotreatment, affects expression, affects methylation	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	decreases reaction, increases acetylation	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases acetylation, affects cotreatment	1
15-deoxyprostaglandin J2	decreases reaction, increases acetylation	1
abrine	increases expression	1
SK-7041	increases acetylation	1
mocetinostat	increases acetylation	1
bis-N,N-dimethylamino-2-(N-methylpyrrolyl)methyl cyclopentadienyl titanium (IV)	decreases expression	1
(+)-JQ1 compound	increases expression	1
Fluticasone	decreases reaction, increases acetylation	1
Salmeterol Xinafoate	decreases reaction, increases acetylation	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2175621	Binding	Binding affinity to fluorescein-labeled Histone H4(1-20) by spectrofluorometry	Pharmacophore-based virtual screening and biological evaluation of small molecule inhibitors for protein arginine methylation. — J Med Chem

Clinical trials (associated diseases)

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