H2AZ1

Summary

H2AZ1 (H2A.Z variant histone 1, HGNC:4741) is a protein-coding gene on chromosome 4q23, encoding Histone H2A.Z (P0C0S5). Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. It is a selective cancer dependency (DepMap: 79.8% of cell lines).

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 encodes a replication-independent member of the histone H2A family that is distinct from other members of the family. Studies in mice have shown that this particular histone is required for embryonic development and indicate that lack of functional histone H2A leads to embryonic lethality.

Source: NCBI Gene 3015 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 11 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 79.8% of screened cell lines
• MANE Select transcript: NM_002106

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4741
Approved symbol	H2AZ1
Name	H2A.Z variant histone 1
Location	4q23
Locus type	gene with protein product
Status	Approved
Aliases	H2A.Z
Ensembl gene	ENSG00000164032
Ensembl biotype	protein_coding
OMIM	142763
Entrez	3015

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000296417, ENST00000511203, ENST00000511319, ENST00000511348, ENST00000527366, ENST00000529158, ENST00000651623, ENST00000853046, ENST00000853047, ENST00000920946, ENST00000920947, ENST00000920948, ENST00000920949, ENST00000920950, ENST00000920951, ENST00000920952, ENST00000920953, ENST00000920954, ENST00000949049

RefSeq mRNA: 1 — MANE Select: NM_002106 NM_002106

CCDS: CCDS3654

Canonical transcript exons

ENST00000296417 — 5 exons

Exon	Start	End
ENSE00001080676	99948088	99948523
ENSE00003643380	99948811	99948940
ENSE00003653685	99949663	99949740
ENSE00003686290	99949273	99949386
ENSE00003843397	99950168	99950275

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 181.7384 / max 2326.7786, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53306	172.4385	1826
53307	7.5302	1724
53309	0.9178	381
53305	0.3487	171
53308	0.2943	130
53310	0.2089	66

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.66	gold quality
embryo	UBERON:0000922	99.62	gold quality
ganglionic eminence	UBERON:0004023	99.59	gold quality
adult organism	UBERON:0007023	99.42	gold quality
gingival epithelium	UBERON:0001949	99.39	gold quality
palpebral conjunctiva	UBERON:0001812	99.38	gold quality
germinal epithelium of ovary	UBERON:0001304	99.31	gold quality
trabecular bone tissue	UBERON:0002483	99.29	gold quality
esophagus squamous epithelium	UBERON:0006920	99.29	gold quality
eye	UBERON:0000970	99.24	gold quality
penis	UBERON:0000989	99.24	gold quality
gingiva	UBERON:0001828	99.19	gold quality
epithelium of esophagus	UBERON:0001976	99.14	gold quality
epithelium of nasopharynx	UBERON:0001951	99.13	gold quality
mucosa of transverse colon	UBERON:0004991	99.13	gold quality
oral cavity	UBERON:0000167	99.12	gold quality
nasopharynx	UBERON:0001728	99.12	gold quality
right testis	UBERON:0004534	99.11	gold quality
bone element	UBERON:0001474	99.09	gold quality
thymus	UBERON:0002370	99.07	gold quality
bone marrow	UBERON:0002371	99.07	gold quality
squamous epithelium	UBERON:0006914	99.07	gold quality
visceral pleura	UBERON:0002401	99.06	gold quality
vermiform appendix	UBERON:0001154	99.05	gold quality
left testis	UBERON:0004533	99.05	gold quality
tongue squamous epithelium	UBERON:0006919	99.05	gold quality
islet of Langerhans	UBERON:0000006	99.03	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.02	gold quality
smooth muscle tissue	UBERON:0001135	99.01	gold quality
caecum	UBERON:0001153	99.01	gold quality

Single-cell (SCXA)

Detected in 79 experiment(s), a significant marker in 49.

Experiment	Marker?	Max mean expression
E-MTAB-6379	yes	11167.33
E-CURD-79	yes	4383.10
E-HCAD-5	yes	3476.85
E-HCAD-10	yes	3383.53
E-MTAB-10662	yes	3361.08
E-MTAB-9906	yes	3289.97
E-MTAB-8221	yes	3162.21
E-HCAD-13	yes	2829.36
E-MTAB-10042	yes	2826.79
E-MTAB-6308	yes	2734.97
E-HCAD-15	yes	2662.00
E-MTAB-6653	yes	2653.18
E-GEOD-139324	yes	2612.88
E-HCAD-6	yes	2601.51
E-MTAB-10287	yes	2498.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF, ESR1, FOXN1, KAT5, MYB, MYC, SMARCA1, SP1, TP63

miRNA regulators (miRDB)

61 targeting H2AZ1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4328	99.57	71.06	4094

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 79.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• chromatin remodeling at the c-myc gene involves the local exchange of histone H2A.Z (PMID:15878876)
• neither H2AZ itself nor other features of the H2AZ-containing nucleosome spread to the neighboring nucleosomes in vivo, arguing against a role for H2AZ as a self-perpetuating epigenetic mark (PMID:16809769)
• identify the essential histone variant H2A.Z as a new structural component of the centromere (PMID:17194760)
• Monoubiquitylation of H2A.z distinguishes its association with euchromatin or facultative heterochromatin. (PMID:17636032)
• Upon DNA damage, histone H2A.Z is first evicted from the p21 promoter, followed by the recruitment of the Tip60 histone acetyltransferase to activate p21 transcription. (PMID:17671089)
• histone variant H2A.Z is associated with breast cancer progression (PMID:18414489)
• Results show that H2A.Z nucleosomes protect only approximately 120 bp of DNA from MNase digestion and exhibit specific sequence preferences, suggesting a novel mechanism of nucleosome organization for the H2A.Z variant. (PMID:19246569)
• Both genetic and epigenetic features are likely to participate in targeting H2A.Z to distinct chromatin loci. (PMID:19261190)
• The nucleosome destabilizing effect of H2A.Z acetylation takes place synergistically with the acetylation of the rest of the core histones. (PMID:19385636)
• H2A.Z is incorporated into the promoter regions of estrogen receptor (ERalpha) target genes only upon gene induction, and that, in a cyclic pattern (PMID:19515975)
• show that upon gene induction, human H2A.Z associates with gene promoters and helps in recruiting the transcriptional machinery. (PMID:19834540)
• Both H2A.Z and H3.3 affect nucleosome positioning, either creating new positions or altering the relative occupancy of the existing nucleosome position space. Only H2A.Z-containing nucleosomes exhibit altered linker histone binding. (PMID:19856965)
• Eesterogen Receptor alpha directly associates to the H2A.Z promoter, and consequently modulates its expression. (PMID:20023423)
• This review provides a brief overview of H2A.Z biology and presents hypotheses that could reconcile contradictory reports that are found in the literature regarding the influence of H2A.Z on nucleosome stability. (PMID:20364108)
• H2A.Z is maintained during mitosis and marks the +1 nucleosome of active genes, which shifts during mitosis, resulting in occupancy at the transcriptional start site and a reduced nucleosome-depleted region. (PMID:20864037)
• acetylation of H2A.Z is a key modification associated with gene activity in normal cells and epigenetic gene deregulation in tumorigenesis. (PMID:21788347)
• nucleosomes containing H2AZ are primarily composed of H4 K12ac and H3 K4me3 but not H3 K36me3 (PMID:22393239)
• The short forms of H2A.Z in both yeast and human cells are more loosely associated with chromatin than the full-length proteins, indicating a conserved function for the H2A.Z C-terminal tail in regulating the association of H2A.Z with nucleosomes. (PMID:22493515)
• ZNF24 may be implicated in transcriptional regulation of genes associated with oncogenesis via interaction with H2A.Z. (PMID:22678762)
• Study mapped H2A.Z genome-wide in embryonic stem cells and neural progenitors; H2A.Z is deposited at promoters and enhancers, and correlates strongly with H3K4 methylation. H2A.Z is present at poised promoters with bivalent chromatin and at active promoters with H3K4 methylation, but is absent from stably repressed promoters that are enriched for H3K27 trimethylation. (PMID:23034477)
• incorporation of the histone variant H2A.Z at the promoter regions of PPARgamma target genes by p400/Brd8 is essential to allow fat cell differentiation (PMID:23064015)
• H2A.Z-dependent crosstalk between enhancer and promoter regulates cyclin D1 expression. (PMID:23108396)
• H2A.Z exchange promotes specific patterns of histone modification and reorganization of the chromatin architecture, leading to the assembly of a chromatin template that is an efficient substrate for the DNA double-strand break repair machinery. (PMID:23122415)
• age-dependent p400 downregulation and loss of H2A.Z localisation may contribute to the onset of replicative senescence through a sustained high rate of p21 transcription (PMID:23146670)
• Data indicate that histone H2A.Z as a protein capable of binding ST1926 specifically. (PMID:23245330)
• SETD6 monomethylates H2AZ on lysine 7. (PMID:23324626)
• Data show that histone deacetylase inhibitors (HDACi) induce p21 transcription and reduce cell proliferation of MDA-MB231, an ERalpha-negative mammary tumor cell line, in a H2A.Z dependent manner. (PMID:23349794)
• Sirt1 and H2A.Z deregulation in prostate cancer are related. Epigenetic mechanisms, mostly histone post-translational modifications, are likely involved and impair sirt1-mediated downregulation of H2A.Z via proteasome-mediated degradation. (PMID:24127549)
• Depletion of H2A.Z in the osteosarcoma U2OS cell line and in immortalized human fibroblasts does not change parameters of DNA double-strand breaks repair while affecting clonogenic ability and cell cycle distribution. (PMID:24240188)
• A mutational analysis revealed that the amino-acid difference at position 38 is at least partially responsible for the structural polymorphism in the L1 loop region of H2A.Z.1 and H2A.Z.2. (PMID:24311584)
• the predictive values regarding low expressions of H2AFZ and CASP8AP2 and high white blood cell count suggest that these features could help to identify more accurately patients at greater risk of relapse. (PMID:24397596)
• Anp32e may help to resolve the non-nucleosomal H2A.Z aggregates and also facilitate the removal of H2A.Z at the +1 nucleosomes, and the latter may help RNA polymerase II to pass the first nucleosomal barrier. (PMID:24613878)
• Results demonstrated male-selective association of the H2AFZ gene with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia (PMID:25392085)
• Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair. (PMID:26034280)
• The findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma. (PMID:26051178)
• H2A.Z removal from chromatin is the primary function of INO80 and ANP32E in promoting homologous recombination. (PMID:26142279)
• the H2AFZ gene may confer a risk for schizophrenia and contribute to the impairment of executive function in Han Chinese patients with schizophrenia. (PMID:26246156)
• Results suggest that the N-terminal tail of H2A.Z makes distinctively different contributions to epigenetic events. (PMID:26833946)
• Findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. (PMID:26863632)
• The 2.7-A-resolution crystal structure of the human YL1-H2A.Z-H2B complex shows that YL1 binding, similarly to ANP32E binding, triggers an extension of the H2A.Z alphaC helix. (PMID:26974126)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
drosophila_melanogaster	His2Av	FBGN0001197

Paralogs (27): MACROH2A2 (ENSG00000099284), H2AZ2 (ENSG00000105968), MACROH2A1 (ENSG00000113648), H2AC1 (ENSG00000164508), H2AC6 (ENSG00000180573), H2AC25 (ENSG00000181218), H2AC20 (ENSG00000184260), H2AC21 (ENSG00000184270), H2AX (ENSG00000188486), H2AC13 (ENSG00000196747), H2AC11 (ENSG00000196787), H2AC7 (ENSG00000196866), H2AL3 (ENSG00000229674), H2AJ (ENSG00000246705), H2AL1Q (ENSG00000249467), H2AB1 (ENSG00000274183), H2AC12 (ENSG00000274997), H2AC15 (ENSG00000275221), H2AC14 (ENSG00000276368), H2AC16 (ENSG00000276903), H2AC8 (ENSG00000277075), H2AB3 (ENSG00000277745), H2AB2 (ENSG00000277858), H2AC4 (ENSG00000278463), H2AC17 (ENSG00000278677), H2AC18 (ENSG00000288825), H2AC19 (ENSG00000288859)

Protein

Protein identifiers

Histone H2A.Z — P0C0S5 (reviewed: P0C0S5)

All UniProt accessions (2): A0A494C189, P0C0S5

UniProt curated annotations — full annotation on UniProt →

Function. Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. 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. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division.

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. H2A or its variant H2AZ1 forms a heterodimer with H2B. H2AZ1 interacts with INCENP. Interacts (via M6 cassette) with ANP32E; leading to removal of H2A.Z/H2AZ1 from the nucleosome. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain). The interaction of HZAZ1 and VPS72 is enhanced by VPS72 phosphorylation which is promoted by ZNHIT1. Interacts with PWWP2A. Interacts with FH (when phosphorylated by PRKDC). Interacts with ZNHIT1; the interaction results in recruitment of H2AZ1 to the MYOG promoter region which is required for muscle-specific gene expression.

Subcellular location. Nucleus. Chromosome.

Post-translational modifications. Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression. Acetylated on Lys-5, Lys-8, Lys-12 and Lys-14 by KAT2A; KAT2A is recruited by the XPC complex in absence of DNA damage. Acetylated on Lys-5, Lys-8 and Lys-12 during interphase; acetylation disappears at mitosis. Acetylation by the NuA4 histone acetyltransferase complex is required for hematopoietic stem cell maintenance. Monomethylated on Lys-5 and Lys-8 by SETD6. SETD6 predominantly methylates Lys-8, lys-5 being a possible secondary site. Not phosphorylated. 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 H2A family.

RefSeq proteins (1): NP_002097* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002119	Histone_H2A	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR032454	Histone_H2A_C	Domain
IPR032458	Histone_H2A_CS	Conserved_site

Pfam: PF00125, PF16211

UniProt features (35 total): modified residue 10, mutagenesis site 7, helix 6, region of interest 5, strand 3, initiator methionine 1, chain 1, cross-link 1, compositionally biased region 1

Structure

Experimental structures (PDB)

28 structures.

PDB	Method	Resolution (Å)
4CAY	X-RAY DIFFRACTION	1.48
6KO2	X-RAY DIFFRACTION	1.5
5CHL	X-RAY DIFFRACTION	1.89
9INC	X-RAY DIFFRACTION	2.01
6JOU	X-RAY DIFFRACTION	2.17
5B31	X-RAY DIFFRACTION	2.2
5B32	X-RAY DIFFRACTION	2.35
5Z30	X-RAY DIFFRACTION	2.45
9UBD	X-RAY DIFFRACTION	2.53
1F66	X-RAY DIFFRACTION	2.6
8T9F	ELECTRON MICROSCOPY	2.6
4NFT	X-RAY DIFFRACTION	2.61
5FUG	X-RAY DIFFRACTION	2.7
9OGR	ELECTRON MICROSCOPY	2.78
9OH0	ELECTRON MICROSCOPY	2.78
5B33	X-RAY DIFFRACTION	2.92
9OGS	ELECTRON MICROSCOPY	3.05
9OGZ	ELECTRON MICROSCOPY	3.05
3WA9	X-RAY DIFFRACTION	3.07
9OH1	ELECTRON MICROSCOPY	3.09
8THU	ELECTRON MICROSCOPY	3.1
9OH2	ELECTRON MICROSCOPY	3.14
7YRD	ELECTRON MICROSCOPY	3.2
9GCG	ELECTRON MICROSCOPY	3.43
9GE4	ELECTRON MICROSCOPY	3.52
8JHF	ELECTRON MICROSCOPY	3.68
7YRG	ELECTRON MICROSCOPY	4.2
9C62	ELECTRON MICROSCOPY	5.28

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0C0S5-F1	90.96	0.82

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 (11): 5, 8, 8, 12, 12, 14, 14, 116, 122, 5, 5

Mutagenesis-validated functional residues (7):

Position	Phenotype
5–14	decreased acetylation by kat2a.
5–8	decreased acetylation by kat2a.
12–14	decreased acetylation by kat2a.
83	decreases interaction with vps72. almost abolishes interaction with vps72; when associated with n-93. abolishes interact
93	decreases interaction with vps72. almost abolishes interaction with vps72; when associated with i-83. abolishes interact
98	no effect on interaction with vps72.
101	abolishes interaction with vps72; when associated with i-83 and n-93.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-977225	Amyloid fiber formation
R-HSA-9970672	FXIIa activates plasma kallikrein-kinin system

MSigDB gene sets: 453 (showing top): AHRARNT_01, E2F_Q4, MORF_DNMT1, E2F_Q4_01, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, MODULE_451, MORF_ESPL1, MORF_SMC1L1, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_RESPONSE_TO_ESTRADIOL, E2F4DP1_01, MORF_BUB1, GOBP_CELLULAR_RESPONSE_TO_LIPID, XU_GH1_AUTOCRINE_TARGETS_UP, GCM_NPM1

GO Biological Process (4): chromatin organization (GO:0006325), heterochromatin formation (GO:0031507), positive regulation of transcription by RNA polymerase II (GO:0045944), cellular response to estradiol stimulus (GO:0071392)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), RNA polymerase II core promoter sequence-specific DNA binding (GO:0000979), structural constituent of chromatin (GO:0030527), chromatin DNA binding (GO:0031490), nucleosomal DNA binding (GO:0031492), protein heterodimerization activity (GO:0046982), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): nucleosome (GO:0000786), euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), extracellular exosome (GO:0070062), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of proteins	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin	4
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
cellular component organization	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
response to estradiol	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cis-regulatory region sequence-specific DNA binding	1
core promoter sequence-specific DNA binding	1
structural molecule activity	1
DNA binding	1
chromatin binding	1
chromatin DNA binding	1
nucleosome binding	1
protein dimerization activity	1
nucleic acid binding	1
binding	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

4504 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
H2AZ1	H2BC21	Q16778	998
H2AZ1	SRCAP	Q6ZRS2	974
H2AZ1	H3-3A	P06351	882
H2AZ1	VPS72	Q15906	864
H2AZ1	EP400	Q96L91	850
H2AZ1	SMARCA2	P51531	835
H2AZ1	H4C16	P02304	816
H2AZ1	KAT5	Q92993	814
H2AZ1	YEATS4	O95619	813
H2AZ1	H3C1	P02295	807
H2AZ1	ZNHIT1	O43257	784
H2AZ1	ANP32E	Q9BTT0	782
H2AZ1	CFDP1	Q9UEE9	777
H2AZ1	SMARCA1	P28370	772
H2AZ1	H3-4	Q16695	740

IntAct

169 interactions, top by confidence:

A	B	Type	Score
BRAF	NRAS	psi-mi:“MI:0914”(association)	0.860
HDAC1	CDK2AP1	psi-mi:“MI:0914”(association)	0.840
H2AZ1	ZNHIT1	psi-mi:“MI:0914”(association)	0.770
ANP32E	H2AZ1	psi-mi:“MI:0914”(association)	0.770
ANP32E	H2AZ1	psi-mi:“MI:0915”(physical association)	0.770
ZNHIT1	H2AZ1	psi-mi:“MI:0915”(physical association)	0.770
H2AZ1	ZNHIT1	psi-mi:“MI:0915”(physical association)	0.770
ZNHIT1	H2AZ1	psi-mi:“MI:0914”(association)	0.770
MBTD1	YEATS4	psi-mi:“MI:0914”(association)	0.730
EPN1	PHGDH	psi-mi:“MI:0914”(association)	0.710
H2AC4	PPM1G	psi-mi:“MI:0914”(association)	0.670
ACTR6	H2AZ1	psi-mi:“MI:0915”(physical association)	0.670
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
RUVBL1	POLR3A	psi-mi:“MI:0914”(association)	0.640
FH	H2AZ1	psi-mi:“MI:0914”(association)	0.620
FH	H2AZ1	psi-mi:“MI:0915”(physical association)	0.620
H2AZ1	H2BC21	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (547): H2AFZ (Affinity Capture-Western), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), BRD3 (Co-fractionation), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), H2AFZ (Proximity Label-MS), H2AFZ (Biochemical Activity), H2AFZ (Biochemical Activity), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS), H2AFZ (Affinity Capture-MS)

ESM2 similar proteins: A1L1L1, A2R702, A4QVR2, G2TRL2, O23628, O62695, O97484, P02272, P02288, P06353, P06902, P08985, P09589, P09590, P0C0S4, P0C0S5, P0C0S6, P0C0S7, P0C5Y9, P0C5Z0, P13630, P16890, P22647, P40285, P48003, P69141, P69142, Q09FM9, Q1DTG2, Q27489, Q2UJ80, Q32LA7, Q3THW5, Q3URR0, Q55BN9, Q5BJ65, Q5EE01, Q5RC42, Q5ZMD6, Q6GM74

Diamond homologs: A1A4R1, A1C5F1, A1CJ10, A1D0C1, A1D8G8, A2R702, A3GHC1, A4QVR2, A5DQL2, A5DXC6, A9UMV8, C0HKE1, L7HZV6, O23628, O62695, O74268, P02272, P02273, P02274, P04735, P04908, P04909, P04910, P08844, P08985, P08991, P08992, P0C0S4, P0C0S5, P0C0S6, P0C0S7, P0C952, P0C953, P0CO00, P0CO01, P0CT12, P13912, P16865, P16866, P22647

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ZNHIT1	unknown	H2AZ1
SLBP	“up-regulates quantity by expression”	H2AZ1	“translation regulation”
DZIP3	“up-regulates activity”	H2AZ1	monoubiquitination
H2AZ1	“form complex”	“Nucleosome_H2A.Z.1 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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
Packaging Of Telomere Ends	12	21.4×	3e-11
Recognition and association of DNA glycosylase with site containing an affected purine	12	19.9×	4e-11
Cleavage of the damaged purine	12	19.9×	4e-11
Replacement of protamines by nucleosomes in the male pronucleus	9	19.9×	1e-08
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	12	18.0×	1e-10
Cleavage of the damaged pyrimidine	12	18.0×	1e-10
Condensation of Prophase Chromosomes	14	17.8×	5e-12
Inhibition of DNA recombination at telomere	13	17.8×	3e-11

GO biological processes:

GO term	Partners	Fold	FDR
regulation of double-strand break repair	7	26.9×	3e-06
innate immune response in mucosa	6	26.8×	2e-05
positive regulation of double-strand break repair via homologous recombination	8	20.3×	3e-06
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	5	13.6×	2e-03
heterochromatin formation	8	13.5×	3e-05
antibacterial humoral response	6	13.1×	6e-04
nucleosome assembly	10	9.3×	3e-05
response to ethanol	9	8.7×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	4
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

612 predictions. Top by Δscore:

Variant	Effect	Δscore
4:99948938:TACC:T	acceptor_loss	1.0000
4:99949269:TTACC:T	donor_loss	1.0000
4:99949270:TACCT:T	donor_loss	1.0000
4:99949271:A:C	donor_loss	1.0000
4:99949272:C:CA	donor_loss	1.0000
4:99949272:CCT:C	donor_gain	1.0000
4:99948521:CAC:C	acceptor_gain	0.9900
4:99948522:ACC:A	acceptor_loss	0.9900
4:99948524:C:G	acceptor_loss	0.9900
4:99948525:T:C	acceptor_loss	0.9900
4:99948805:ACAT:A	donor_loss	0.9900
4:99948808:TA:T	donor_loss	0.9900
4:99948809:A:AT	donor_loss	0.9900
4:99949387:C:CC	acceptor_gain	0.9900
4:99949388:T:C	acceptor_gain	0.9900
4:99949388:T:TC	acceptor_gain	0.9900
4:99949395:T:C	acceptor_gain	0.9900
4:99949400:C:CT	acceptor_gain	0.9900
4:99949401:A:AC	acceptor_gain	0.9900
4:99949401:A:C	acceptor_gain	0.9900
4:99949660:GA:G	donor_loss	0.9900
4:99949661:A:T	donor_loss	0.9900
4:99949759:C:CT	acceptor_gain	0.9900
4:99949759:C:T	acceptor_gain	0.9900
4:99949765:C:CT	acceptor_gain	0.9900
4:99949766:G:T	acceptor_gain	0.9900
4:99950246:A:AC	donor_gain	0.9900
4:99950246:ACT:A	donor_gain	0.9900
4:99950247:C:CC	donor_gain	0.9900
4:99950247:CTC:C	donor_gain	0.9900

AlphaMissense

808 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:99948822:A:T	I105N	1.000
4:99948846:A:G	L97S	1.000
4:99948855:T:A	D94V	1.000
4:99948855:T:G	D94A	1.000
4:99948856:C:G	D94H	1.000
4:99948864:A:T	I91N	1.000
4:99948867:G:T	A90D	1.000
4:99948870:A:G	L89P	1.000
4:99948924:C:A	G71V	1.000
4:99948924:C:T	G71E	1.000
4:99948925:C:G	G71R	1.000
4:99948925:C:T	G71R	1.000
4:99948930:A:G	L69P	1.000
4:99948934:C:T	E68K	1.000
4:99948936:A:G	L67P	1.000
4:99949278:C:G	A64P	1.000
4:99949283:A:G	L62P	1.000
4:99949287:A:G	Y61H	1.000
4:99949289:T:A	E60V	1.000
4:99949298:G:T	A57D	1.000
4:99949299:C:G	A57P	1.000
4:99949316:G:T	A51D	1.000
4:99949385:A:G	F28S	1.000
4:99949667:A:C	L26W	1.000
4:99948496:A:G	L118P	0.999
4:99948508:A:T	I114N	0.999
4:99948523:C:A	G109V	0.999
4:99948523:C:T	G109D	0.999
4:99948811:C:A	G109C	0.999
4:99948811:C:G	G109R	0.999

dbSNP variants (sampled 300 via entrez): RS1000269871 (4:99947648 C>T), RS1000955299 (4:99950229 G>A,C,T), RS1002192955 (4:99949058 T>A), RS1003079407 (4:99950275 C>A,T), RS1003273611 (4:99951558 C>T), RS1003626435 (4:99951526 A>C,G), RS1003657721 (4:99950324 A>C,T), RS1006161759 (4:99950958 T>A), RS1006375244 (4:99950480 A>G,T), RS1006945407 (4:99952269 T>G), RS1007337389 (4:99947986 T>C), RS1007374174 (4:99950690 A>G), RS1007692850 (4:99950927 C>T), RS1008958612 (4:99949898 C>T), RS1010103746 (4:99949759 C>A,G)

Disease associations

OMIM: gene MIM:142763 | 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): CHEMBL5724668 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	increases expression	2
cobaltous chloride	decreases expression	2
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Rotenone	decreases expression, increases expression	2
Cyclosporine	decreases expression, increases expression	2
Genistein	increases expression, decreases expression, increases reaction	2
Particulate Matter	decreases expression, increases abundance	2
dicrotophos	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
diallyl trisulfide	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
chloropicrin	affects expression	1
K 7174	decreases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
3-(4’-hydroxy-3’-adamantylbiphenyl-4-yl)acrylic acid	decreases expression	1
pyrimidifen	increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1
Dasatinib	decreases expression	1
Fulvestrant	decreases expression	1
Leflunomide	decreases expression	1
Aminoglutethimide	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697223	Binding	Inhibition of H2AFZ (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

6 cell lines: 3 embryonic stem cell, 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2K8	SEES3-1V human H2AFZ, clone1	Embryonic stem cell	Male
CVCL_A2K9	SEES3-1V human H2AFZ, clone2	Embryonic stem cell	Male
CVCL_A2L0	SEES3-1V human H2AFZ, clone3	Embryonic stem cell	Male
CVCL_SQ77	HAP1 H2AFZ (-) 1	Cancer cell line	Male
CVCL_SQ78	HAP1 H2AFZ (-) 2	Cancer cell line	Male
CVCL_SQ79	HAP1 H2AFZ (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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