MACROH2A1

Summary

MACROH2A1 (macroH2A.1 histone, HGNC:4740) is a protein-coding gene on chromosome 5q31.1, encoding Core histone macro-H2A.1 (O75367). Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription.

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 histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and participates in stable X chromosome inactivation. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 9555 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brachydactyly-elbow wrist dysplasia syndrome (Supportive, GenCC)
• GWAS associations: 12
• Clinical variants (ClinVar): 32 total — 1 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_138610

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4740
Approved symbol	MACROH2A1
Name	macroH2A.1 histone
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	macroH2A1.2
Ensembl gene	ENSG00000113648
Ensembl biotype	protein_coding
OMIM	610054
Entrez	9555

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 36 protein_coding, 7 protein_coding_CDS_not_defined, 6 retained_intron, 3 nonsense_mediated_decay

ENST00000304332, ENST00000312469, ENST00000360597, ENST00000423969, ENST00000451949, ENST00000504197, ENST00000505827, ENST00000506218, ENST00000506532, ENST00000506671, ENST00000507868, ENST00000508120, ENST00000508785, ENST00000508962, ENST00000510038, ENST00000511494, ENST00000511689, ENST00000512507, ENST00000513210, ENST00000513268, ENST00000687629, ENST00000688649, ENST00000877620, ENST00000877621, ENST00000877622, ENST00000877623, ENST00000877624, ENST00000877625, ENST00000877626, ENST00000877627, ENST00000877628, ENST00000877629, ENST00000877630, ENST00000877631, ENST00000877632, ENST00000923034, ENST00000923035, ENST00000923036, ENST00000923037, ENST00000923038, ENST00000923039, ENST00000953736, ENST00000953737, ENST00000953738, ENST00000953739, ENST00000953740, ENST00000953741, ENST00000953742, ENST00000953743, ENST00000953744, ENST00000953745, ENST00000953746

RefSeq mRNA: 8 — MANE Select: NM_138610 NM_001040158, NM_001400401, NM_001400402, NM_001400403, NM_001400404, NM_004893, NM_138609, NM_138610

CCDS: CCDS4183, CCDS4184, CCDS4185, CCDS93784

Canonical transcript exons

ENST00000511689 — 9 exons

Exon	Start	End
ENSE00000763579	135352946	135353045
ENSE00002063464	135399062	135399231
ENSE00002078302	135334381	135335141
ENSE00003473817	135345968	135346057
ENSE00003491339	135388922	135389126
ENSE00003507098	135343260	135343434
ENSE00003509787	135370036	135370142
ENSE00003543735	135369406	135369603
ENSE00003554969	135360497	135360607

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 94.1225 / max 1916.1109, expressed in 1826 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63529	71.7145	1826
63530	9.6692	1772
63527	6.7648	1645
63528	1.9370	1142
63532	1.2787	109
63524	0.7760	424
63526	0.7571	452
63523	0.6756	402
63525	0.2482	111
63531	0.2053	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelium of nasopharynx	UBERON:0001951	99.39	gold quality
tongue squamous epithelium	UBERON:0006919	99.23	gold quality
monocyte	CL:0000576	99.20	gold quality
mononuclear cell	CL:0000842	99.19	gold quality
leukocyte	CL:0000738	99.13	gold quality
pharyngeal mucosa	UBERON:0000355	99.10	gold quality
penis	UBERON:0000989	99.08	gold quality
esophagus squamous epithelium	UBERON:0006920	99.06	gold quality
trabecular bone tissue	UBERON:0002483	99.03	gold quality
buccal mucosa cell	CL:0002336	99.01	gold quality
ganglionic eminence	UBERON:0004023	99.01	gold quality
epithelium of esophagus	UBERON:0001976	98.97	gold quality
amniotic fluid	UBERON:0000173	98.88	gold quality
palpebral conjunctiva	UBERON:0001812	98.87	gold quality
lower lobe of lung	UBERON:0008949	98.86	gold quality
gingiva	UBERON:0001828	98.85	gold quality
embryo	UBERON:0000922	98.83	gold quality
bone element	UBERON:0001474	98.83	gold quality
bone marrow	UBERON:0002371	98.82	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.82	gold quality
gingival epithelium	UBERON:0001949	98.81	gold quality
ventricular zone	UBERON:0003053	98.81	gold quality
squamous epithelium	UBERON:0006914	98.79	gold quality
colonic mucosa	UBERON:0000317	98.78	gold quality
bronchial epithelial cell	CL:0002328	98.67	gold quality
oral cavity	UBERON:0000167	98.65	gold quality
mammalian vulva	UBERON:0000997	98.61	gold quality
blood	UBERON:0000178	98.60	gold quality
eye	UBERON:0000970	98.54	gold quality
esophagus mucosa	UBERON:0002469	98.54	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 15.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	719.33
E-CURD-112	yes	49.30
E-MTAB-10553	yes	34.43
E-HCAD-10	yes	34.42
E-CURD-46	yes	33.05
E-MTAB-9221	yes	28.52
E-MTAB-6701	yes	24.03
E-CURD-122	yes	23.89
E-CURD-88	yes	21.09
E-HCAD-1	yes	18.16
E-MTAB-8410	yes	14.45
E-MTAB-9467	yes	13.31
E-MTAB-10042	yes	11.26
E-CURD-114	yes	7.74
E-HCAD-32	no	494.50

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting MACROH2A1, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 40)

• distributed during the maintainance phase of x inactivation throughout cell cycle (PMID:12082075)
• MACROH2A1 deposition is regulated by the CULLIN3/SPOP ligase complex and is actively involved in stable X inactivation. (PMID:15897469)
• A specific interaction between mH2A1.1 and PARP-1 was demonstrated and found to be associated with inactivation of PARP-1 enzymatic activity. (PMID:17158748)
• multiple short sequences dispersed along the macroH2A1 histone domain individually supported enrichment on the inactive X chromosome when introduced into H2A (PMID:17570398)
• A phosphorylation site, S137ph, was identified in mH2A1;S137ph is enriched in mitosis. (PMID:18227505)
• expression of histone macroH2A1.1 and macroH2A2 predicts lung cancer recurrence. (PMID:19648962)
• show that distinct macrodomains, including those of histone macroH2A1.1, are recruited to sites of PARP1 activation induced by laser-generated DNA damage. (PMID:19680243)
• an unexpected role for macroH2A1 in the escape from heterochromatin-associated silencing and the enhancement of autosomal gene transcription (PMID:20008927)
• macroH2A can play either a positive or negative role in transcriptional regulation in a context-dependent manner. Additionally, macroH2A has been linked to the control of the cell cycle and cell proliferation. (PMID:20543561)
• significant inverse correlation between mH2A and CDK8 expression levels exists in melanoma patient samples (PMID:21179167)
• QKI, regulates the alternative splicing of macroH2A1 pre-mRNA, resulting in increased levels of macroH2A1.1. (PMID:21844227)
• H2AFY is specifically overexpressed in the blood and frontal cortex of patients with Huntington disease compared with controls (PMID:21969577)
• direct interaction and binding features between VRK1 and macroH2A1.2 (PMID:22194607)
• ATRX (alpha-thalassemia/MR, X-linked) is a novel macroH2A-interacting protein (PMID:22391447)
• Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation. (PMID:22589551)
• MacroH2A1 splicing isoforms differentially regulate the transcription of a set of genes involved in redox metabolism. (PMID:23022728)
• The histone variant macroH2A1.1 is recruited to DNA double-strand breaks through a mechanism involving PARP1. (PMID:23031826)
• Both macroH2A1 isoforms may play a role in hepatocellular carcinoma pathogenesis and may be considered as novel diagnostic markers for human hepatocellular carcinoma. (PMID:23372727)
• macro histone variants (macroH2A) are expressed at low levels in stem cells and are up-regulated during differentiation (PMID:23595991)
• The results demonstrate that macroH2A1 is a new factor involved in the regulation of rDNA transcription. (PMID:24071584)
• MacroH2A1 specifically recruits PELP1 to the promoters of macroH2A1 target genes, but macroH2A1 occupancy occurs independent of PELP1. This recruitment allows macroH2A1 and PELP1 to cooperatively regulate gene expression outcomes. (PMID:24752897)
• macroH2A1.1 expression correlates with poor survival of triple-negative breast cancer patients (PMID:24911873)
• MacroH2A1.1 and PARP-1 cooperate to regulate transcription by promoting CBP-mediated H2B acetylation. (PMID:25306110)
• High MacroH2A1 expression is associated with epigenetic markers for activation of lipogenic genes in fat-induced steatosis. (PMID:25526730)
• The Skp2-mH2A1-CDK8 axis has a critical role in breast cancer development via dysregulation of the G2/M transition, polyploidy, cell growth dysregulation, and loss of tumor suppression. (PMID:25818643)
• We show that composite nucleosomes containing mH2A and NRF-1 are stably positioned on gene regulatory regions and can buffer transcriptional noise associated with antiviral responses (PMID:25959814)
• This article points to a splicing-regulated, proto-oncogenic role for the macroH2A1.2 variant and suggests manipulation of macroH2A1.2 expression as a potential therapeutic means to interfere with tumorigenesis. (PMID:29249653)
• data uncover a new and specific role for mH2A1.2 in modulating osteoclastogenic potential of prostate cancer cells and demonstrate how this signaling pathway can be exploited to treat osteolytic bone metastases at the molecular level. (PMID:29925860)
• macroH2A1.2 physically and functionally interacts with the histone methyltransferase EZH2 and elevates Histone 3 lysine 27 trimethylation levels to keep LOX gene in a repressed state. (PMID:29972783)
• Data show that macroH2A1 incorporation into H2B-acetylated chromatin requires a feature in its histone-fold domain. (PMID:30510186)
• Our data indicate that housekeeping promoters may titrate promiscuous enhancer activity to ensure normal morphogenesis. The deletion of the H2AFY promoter as a cause of Liebenberg syndrome highlights this new mutational mechanism and its role in congenital disease. (PMID:30711920)
• The findings identify the dynamic exchange of macroH2A1.2 on chromatin as an epigenetic link among ATRX loss, replication stress-induced DNA damage response initiation and telomere maintenance via homologous recombination. (PMID:30833786)
• Results found that macroH2A1 isoforms’ mRNA levels are significantly decreased in yyelodysplastic syndromes (MDS) patients with a 5q deletion compared to other MDS groups and healthy individuals. (PMID:31439048)
• CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity. (PMID:31488827)
• These results demonstrate that, conversely, macrodomain-containing proteins, and specifically those containing macroH2A1, can regulate PARP1 function through a novel mechanism that promotes both survival and efficient repair during DNA damage response. (PMID:31636161)
• Loss of histone macroH2A1 in hepatocellular carcinoma cells promotes paracrine-mediated chemoresistance and CD4(+)CD25(+)FoxP3(+) regulatory T cells activation. (PMID:31903159)
• Histone H2A variants alpha1-extension helix directs RNF168-mediated ubiquitination. (PMID:32424115)
• Upregulated mH2A1 serves as an unfavorable prognostic indicator and promotes the progress of hepatocellular carcinoma (HCC). (PMID:33058912)
• Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions. (PMID:34003252)
• The epigenetic regulator LSH maintains fork protection and genomic stability via MacroH2A deposition and RAD51 filament formation. (PMID:34112784)

Cross-species orthologs

23 orthologs

Organism	Symbol	Gene ID
danio_rerio	macroh2a1	ENSDARG00000099329
mus_musculus	Macroh2a1	ENSMUSG00000015937
rattus_norvegicus	Macroh2a1	ENSRNOG00000011523
drosophila_melanogaster	His2A:CG31618	FBGN0051618
drosophila_melanogaster	His2A:CG33808	FBGN0053808
drosophila_melanogaster	His2A:CG33814	FBGN0053814
drosophila_melanogaster	His2A:CG33817	FBGN0053817
drosophila_melanogaster	His2A:CG33820	FBGN0053820
drosophila_melanogaster	His2A:CG33823	FBGN0053823
drosophila_melanogaster	His2A:CG33826	FBGN0053826
drosophila_melanogaster	His2A:CG33829	FBGN0053829
drosophila_melanogaster	His2A:CG33832	FBGN0053832
drosophila_melanogaster	His2A:CG33835	FBGN0053835
drosophila_melanogaster	His2A:CG33838	FBGN0053838
drosophila_melanogaster	His2A:CG33841	FBGN0053841
drosophila_melanogaster	His2A:CG33844	FBGN0053844
drosophila_melanogaster	His2A:CG33847	FBGN0053847
drosophila_melanogaster	His2A:CG33850	FBGN0053850
drosophila_melanogaster	His2A:CG33853	FBGN0053853
drosophila_melanogaster	His2A:CG33856	FBGN0053856
drosophila_melanogaster	His2A:CG33859	FBGN0053859
drosophila_melanogaster	His2A:CG33862	FBGN0053862
drosophila_melanogaster	His2A:CG33865	FBGN0053865

Paralogs (27): MACROH2A2 (ENSG00000099284), H2AZ2 (ENSG00000105968), H2AZ1 (ENSG00000164032), 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

Core histone macro-H2A.1 — O75367 (reviewed: O75367)

Alternative names: Histone H2A.y, Medulloblastoma antigen MU-MB-50.205

All UniProt accessions (6): O75367, A0A8I5KRC6, A0A8I5KS04, A0A994J4J7, B4DJC3, D6RCF2

UniProt curated annotations — full annotation on UniProt →

Function. Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. 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. Involved in stable X chromosome inactivation. Inhibits the binding of transcription factors, including NF-kappa-B, and interferes with the activity of remodeling SWI/SNF complexes. Inhibits histone acetylation by EP300 and recruits class I HDACs, which induces a hypoacetylated state of chromatin. Isoform that specifically binds poly-ADP-ribose and O-acetyl-ADP-ribose and plays a key role in NAD(+) metabolism. Able to bind to the ends of poly-ADP-ribose chains created by PARP1 and cap them. This prevents PARP1 from further addition of ADP-ribose and thus limits the consumption of nuclear NAD(+), allowing the cell to maintain proper NAD(+) levels in both the nucleus and the mitochondria to promote proper mitochondrial respiration. Increases the expression of genes involved in redox metabolism, including SOD3. In contrast to isoform 1, does not bind poly-ADP-ribose. Represses SOD3 gene expression.

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. Interacts with HDAC1 and HDAC2. Interacts with SPOP. Part of a complex consisting of MACROH2A1, CUL3 and SPOP. Interacts with PARP1.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. Widely expressed.

Post-translational modifications. Monoubiquitinated at either Lys-116 or Lys-117. May also be polyubiquitinated. Ubiquitination is mediated by the CUL3/SPOP E3 complex and does not promote proteasomal degradation. Instead, it is required for enrichment in inactive X chromosome chromatin.

Domain organisation. The macro domain specifically binds poly-ADP-ribose.

Miscellaneous. The preferential expression of isoform 2 over that of isoform 1 requires the presence of DDX5/DDX17. Preferentially expressed over isoform 2 in the absence of DDX5/DDX17.

Similarity. Belongs to the histone H2A family.

Isoforms (3)

UniProt ID	Names	Canonical?
O75367-2	1, mH2A1.1	yes
O75367-1	2, mH2A1.2
O75367-3	3

RefSeq proteins (8): NP_001035248, NP_001387330, NP_001387331, NP_001387332, NP_001387333, NP_004884, NP_613075, NP_613258* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002119	Histone_H2A	Family
IPR002589	Macro_dom	Domain
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily
IPR021171	Core_histone_macro-H2A	Family
IPR032454	Histone_H2A_C	Domain
IPR035796	Macro_H2A	Domain
IPR043472	Macro_dom-like	Homologous_superfamily

Pfam: PF00125, PF01661, PF16211

UniProt features (59 total): strand 14, helix 11, modified residue 10, binding site 8, cross-link 6, domain 2, splice variant 2, sequence conflict 2, chain 1, region of interest 1, compositionally biased region 1, turn 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
3HSV	X-RAY DIFFRACTION	1.43
1ZR3	X-RAY DIFFRACTION	1.66
3IVB	X-RAY DIFFRACTION	1.75
3IID	X-RAY DIFFRACTION	1.9
3IIF	X-RAY DIFFRACTION	2.1
5IIT	X-RAY DIFFRACTION	2.13
3HQH	X-RAY DIFFRACTION	2.3
2FXK	X-RAY DIFFRACTION	2.54
2F8N	X-RAY DIFFRACTION	2.9
1ZR5	X-RAY DIFFRACTION	2.92
1U35	X-RAY DIFFRACTION	3
7D3Y	X-RAY DIFFRACTION	3.11
5LNC	X-RAY DIFFRACTION	3.29

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75367-F1	83.40	0.69

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (8): 313; 314; 316; 203; 204; 226; 275; 312

Post-translational modifications (16): 7, 9, 18, 116, 123, 123, 129, 170, 173, 178, 116, 117, 123, 167, 189, 320

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 473 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_CHROMOSOME_ORGANIZATION, AGGAAGC_MIR5163P, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, HNF3ALPHA_Q6, GOBP_POSITIVE_REGULATION_OF_KERATINOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, MODULE_151, AREB6_03, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_CELL_CYCLE_PHASE_TRANSITION, MORF_HDAC1, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS

GO Biological Process (23): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of oxidative phosphorylation (GO:0002082), DNA repair (GO:0006281), nucleosome assembly (GO:0006334), dosage compensation by inactivation of X chromosome (GO:0009048), regulation of lipid metabolic process (GO:0019216), heterochromatin formation (GO:0031507), positive regulation of maintenance of mitotic sister chromatid cohesion (GO:0034184), epigenetic regulation of gene expression (GO:0040029), positive regulation of keratinocyte differentiation (GO:0045618), negative regulation of gene expression, epigenetic (GO:0045814), transcription initiation-coupled chromatin remodeling (GO:0045815), protein poly-ADP-ribosylation (GO:0070212), establishment of protein localization to chromatin (GO:0071169), negative regulation of transcription of nucleolar large rRNA by RNA polymerase I (GO:1901837), regulation of NAD metabolic process (GO:1902688), negative regulation of cell cycle G2/M phase transition (GO:1902750), regulation of response to oxidative stress (GO:1902882), negative regulation of response to oxidative stress (GO:1902883), positive regulation of response to oxidative stress (GO:1902884), positive regulation of endodermal cell differentiation (GO:1903226), negative regulation of protein localization to chromosome, telomeric region (GO:1904815), chromatin organization (GO:0006325)

GO Molecular Function (18): rDNA binding (GO:0000182), transcription cis-regulatory region binding (GO:0000976), RNA polymerase II transcription regulatory region sequence-specific DNA binding (GO:0000977), DNA binding (GO:0003677), double-stranded methylated DNA binding (GO:0010385), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein serine/threonine kinase inhibitor activity (GO:0030291), structural constituent of chromatin (GO:0030527), chromatin DNA binding (GO:0031490), nucleosomal DNA binding (GO:0031492), protein heterodimerization activity (GO:0046982), ADP-D-ribose binding (GO:0072570), ADP-D-ribose modification-dependent protein binding (GO:0160002), poly-ADP-D-ribose modification-dependent protein binding (GO:0160004), promoter-specific chromatin binding (GO:1990841), chromatin binding (GO:0003682), protein binding (GO:0005515)

GO Cellular Component (14): nuclear chromosome (GO:0000228), chromosome, telomeric region (GO:0000781), chromatin (GO:0000785), nucleosome (GO:0000786), condensed chromosome (GO:0000793), sex chromatin (GO:0001739), Barr body (GO:0001740), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), nucleolus (GO:0005730), extracellular exosome (GO:0070062), site of DNA damage (GO:0090734), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromosome	4
response to oxidative stress	3
nuclear lumen	3
cellular anatomical structure	3
regulation of response to oxidative stress	2
sequence-specific double-stranded DNA binding	2
chromatin	2
chromatin binding	2
binding	2
heterochromatin	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
oxidative phosphorylation	1
regulation of aerobic respiration	1
DNA metabolic process	1
DNA damage response	1
chromatin organization	1
nucleosome organization	1
protein-DNA complex assembly	1
sex-chromosome dosage compensation	1
heterochromatin formation	1
lipid metabolic process	1
regulation of primary metabolic process	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
maintenance of mitotic sister chromatid cohesion	1
positive regulation of maintenance of sister chromatid cohesion	1
regulation of maintenance of mitotic sister chromatid cohesion	1
chromatin remodeling	1
regulation of gene expression	1
keratinocyte differentiation	1
positive regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
positive regulation of multicellular organismal process	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1

Protein interactions and networks

STRING

2171 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MACROH2A1	PARP1	P09874	885
MACROH2A1	TNKS	O95271	781
MACROH2A1	H2BC21	Q16778	699
MACROH2A1	APLF	Q8IW19	639
MACROH2A1	SUV39H1	O43463	590
MACROH2A1	VRK1	Q99986	583
MACROH2A1	SPOP	O43791	582
MACROH2A1	HDAC1	Q13547	575
MACROH2A1	PARG	Q86W56	565
MACROH2A1	DTX3L	Q8TDB6	549
MACROH2A1	SIRT7	Q9NRC8	545
MACROH2A1	KDM5B	Q9UGL1	511
MACROH2A1	H3C1	P02295	508
MACROH2A1	H3-3A	P06351	505
MACROH2A1	TP53	P04637	488

IntAct

252 interactions, top by confidence:

A	B	Type	Score
XPC	CETN3	psi-mi:“MI:0914”(association)	0.730
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
ERICH2	MACROH2A1	psi-mi:“MI:0915”(physical association)	0.720
MACROH2A1	ERICH2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
H2BC1	PPM1G	psi-mi:“MI:0914”(association)	0.640
NPM1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.610
MACROH2A1	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	MACROH2A1	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	H2BC15	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	NKAPD1	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	VCX2	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	SREK1IP1	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	FAM133A	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	ZNF622	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	TRIM26	psi-mi:“MI:0915”(physical association)	0.560
MACROH2A1	PARP1	psi-mi:“MI:0914”(association)	0.530
MED27	POLR2D	psi-mi:“MI:0914”(association)	0.530
MACROH2A2	PPM1G	psi-mi:“MI:0914”(association)	0.530
H2BC26	PPM1G	psi-mi:“MI:0914”(association)	0.530
H2AC20	PPM1G	psi-mi:“MI:0914”(association)	0.530
HSD3B2	NARS1	psi-mi:“MI:0914”(association)	0.530
C1orf174	AHCYL1	psi-mi:“MI:0914”(association)	0.530

BioGRID (624): ERICH2 (Two-hybrid), H2AFY (Affinity Capture-RNA), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-MS), H2AFY (Affinity Capture-Western)

ESM2 similar proteins: A0A097I2B5, A0A097I2D0, A0A1W2PP81, A0A1W2PPE2, A0A1W2PPH5, A0A1W2PR64, A0A1W2PRV1, A6NLC8, O75367, O93327, P02276, P06898, P0DW11, P0DW12, P0DW13, P0DW14, P25469, P35066, P35067, P40284, P40287, P61830, P61831, P61833, P61836, P81196, P81198, P81201, P81202, P93354, Q00715, Q02874, Q06196, Q0U1A0, Q2HU65, Q43213, Q54LP8, Q54WG6, Q6C0C4, Q757N1

Diamond homologs: A0A0D2UG83, A1A4R1, A1CJ10, A1D8G8, A9UMV8, C0HKE1, C0HKE2, C0HKE3, C0HKE4, C0HKE5, C0HKE6, C0HKE7, C0HKE8, C0HKE9, L7HZV6, O74268, O75367, O93327, P02262, P02263, P02264, P02268, P02269, P02270, P04735, P04908, P06897, P07793, P08844, P09588, P0C0S8, P0C0S9, P0C169, P0C170, P0C952, P0C953, P0CC09, P0CN98, P0CN99, P0CT12

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
SPOP	“up-regulates activity”	MACROH2A1	binding
“Cullin 3-RBX1-Skp1”	“up-regulates activity”	MACROH2A1	monoubiquitination
TRIM59	down-regulates	MACROH2A1	ubiquitination
BRCA1	“up-regulates activity”	MACROH2A1	ubiquitination
MACROH2A1	down-regulates	rRNA_transcription
TRIM59	“down-regulates quantity by destabilization”	MACROH2A1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 201 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	25.8×	2e-05
Packaging Of Telomere Ends	10	16.9×	4e-08
Replacement of protamines by nucleosomes in the male pronucleus	8	16.7×	5e-07
Recognition and association of DNA glycosylase with site containing an affected purine	10	15.7×	4e-08
Cleavage of the damaged purine	10	15.7×	4e-08
Inhibition of DNA recombination at telomere	12	15.5×	1e-08
FXIIa activates plasma kallikrein-kinin system	11	14.6×	3e-08
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	10	14.2×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
heterochromatin formation	11	16.3×	8e-08
cell surface receptor protein tyrosine kinase signaling pathway	11	11.1×	2e-06
nucleosome assembly	13	10.6×	2e-07
cytoplasmic translation	7	7.5×	7e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	11	5.0×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	19
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4685468	NM_138610.3(MACROH2A1):c.80G>A (p.Arg27Gln)	Likely pathogenic

SpliceAI

1809 predictions. Top by Δscore:

Variant	Effect	Δscore
5:135335137:CGTTC:C	acceptor_gain	1.0000
5:135343432:CAG:C	acceptor_gain	1.0000
5:135343435:C:CC	acceptor_gain	1.0000
5:135343441:G:C	acceptor_gain	1.0000
5:135343441:G:GC	acceptor_gain	1.0000
5:135343449:A:AC	acceptor_gain	1.0000
5:135345969:T:TA	donor_gain	1.0000
5:135345979:T:TA	donor_gain	1.0000
5:135369608:C:CT	acceptor_gain	1.0000
5:135369609:A:T	acceptor_gain	1.0000
5:135370033:TA:T	donor_loss	1.0000
5:135370035:C:CT	donor_loss	1.0000
5:135370138:CTCCG:C	acceptor_gain	1.0000
5:135370139:TCCG:T	acceptor_gain	1.0000
5:135370140:CCG:C	acceptor_gain	1.0000
5:135370140:CCGC:C	acceptor_gain	1.0000
5:135370141:CG:C	acceptor_gain	1.0000
5:135370141:CGC:C	acceptor_gain	1.0000
5:135370142:GCTG:G	acceptor_loss	1.0000
5:135370143:C:CA	acceptor_loss	1.0000
5:135370143:C:CC	acceptor_gain	1.0000
5:135370144:T:G	acceptor_loss	1.0000
5:135370145:G:C	acceptor_gain	1.0000
5:135388917:CTCA:C	donor_loss	1.0000
5:135388918:TCACC:T	donor_loss	1.0000
5:135388919:CACCT:C	donor_loss	1.0000
5:135388920:A:AC	donor_gain	1.0000
5:135388921:C:CC	donor_gain	1.0000
5:135388921:C:CG	donor_loss	1.0000
5:135388921:CCTGT:C	donor_gain	1.0000

AlphaMissense

2421 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:135335021:A:C	S358R	1.000
5:135335021:A:T	S358R	1.000
5:135335023:T:G	S358R	1.000
5:135335098:C:G	A333P	1.000
5:135335103:A:G	L331P	1.000
5:135335115:G:T	A327D	1.000
5:135335133:A:G	F321S	1.000
5:135343284:G:T	A310E	1.000
5:135343311:G:T	A301D	1.000
5:135343320:A:G	L298S	1.000
5:135343322:G:C	C297W	1.000
5:135343324:A:G	C297R	1.000
5:135343385:A:C	C276W	1.000
5:135353038:A:G	L199P	1.000
5:135353044:A:G	L197P	1.000
5:135369542:A:G	L114P	1.000
5:135369545:A:C	L113W	1.000
5:135369545:A:G	L113S	1.000
5:135369557:A:C	I109S	1.000
5:135369557:A:G	I109T	1.000
5:135369557:A:T	I109N	1.000
5:135369563:G:C	P107R	1.000
5:135369563:G:T	P107H	1.000
5:135369564:G:A	P107S	1.000
5:135369564:G:T	P107T	1.000
5:135369566:A:G	L106S	1.000
5:135369572:C:A	G104V	1.000
5:135369572:C:T	G104D	1.000
5:135369573:C:A	G104C	1.000
5:135369573:C:G	G104R	1.000

dbSNP variants (sampled 300 via entrez): RS1000073240 (5:135380749 A>C), RS1000136209 (5:135370449 A>G), RS1000196492 (5:135379951 C>T), RS1000251568 (5:135393596 A>G), RS1000333243 (5:135340443 T>C), RS1000359404 (5:135386501 T>C), RS1000366929 (5:135386226 C>T), RS1000397782 (5:135383704 T>G), RS1000409158 (5:135383904 T>A,C), RS1000435093 (5:135363015 C>A,G,T), RS1000507649 (5:135341805 A>G), RS1000560005 (5:135336100 A>G), RS1000569368 (5:135381043 G>A,C), RS1000600254 (5:135334931 C>G,T), RS1000610920 (5:135341149 G>A,T)

Disease associations

OMIM: gene MIM:610054 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
brachydactyly-elbow wrist dysplasia syndrome	Supportive	Autosomal dominant

Mondo (1): brachydactyly-elbow wrist dysplasia syndrome (MONDO:0008520)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000256	Macrocephaly
HP:0001156	Brachydactyly
HP:0001231	Abnormal fingernail morphology
HP:0001387	Joint stiffness
HP:0003042	Elbow dislocation
HP:0004209	Clinodactyly of the 5th finger
HP:0005048	Synostosis of carpal bones
HP:0006501	Aplasia/Hypoplasia of the radius
HP:0009832	Abnormal distal phalanx morphology of finger
HP:0031095	Abnormal humerus morphology
HP:0040071	Abnormal morphology of ulna

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST001060_7	AIDS progression	6.000000e-06
GCST001547_2	Immune response to anthrax vaccine	4.000000e-06
GCST001762_279	Obesity-related traits	6.000000e-06
GCST004627_65	Lymphocyte count	1.000000e-12
GCST007507_9	Benign prostatic hyperplasia and lower urinary tract symptoms	3.000000e-11
GCST007856_79	Colorectal cancer or advanced adenoma	5.000000e-15
GCST010396_27	Gut microbiota (bacterial taxa, hurdle binary method)	6.000000e-06
GCST90002388_325	Lymphocyte count	2.000000e-33
GCST90002389_264	Lymphocyte percentage of white cells	3.000000e-16
GCST90002395_461	Mean platelet volume	2.000000e-15
GCST90002399_424	Neutrophil percentage of white cells	4.000000e-11
GCST90002407_468	White blood cell count	2.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0005119	antioxidant measurement
EFO:0004587	lymphocyte count
EFO:0008008	lower urinary tract symptom
EFO:0007874	gut microbiome measurement
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566090	Synostosis, Carpal, with Dysplastic Elbow Joints and Brachydactyly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, decreases expression, affects expression	8
bisphenol A	affects cotreatment, decreases expression, decreases methylation, increases expression	3
trichostatin A	affects cotreatment, decreases expression	3
Doxorubicin	affects expression, increases expression, affects response to substance	3
sodium arsenite	affects expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
belinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Arsenic	affects methylation, increases ubiquitination	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
sodium arsenate	decreases expression	1
hydroquinone	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
bisphenol AF	increases expression	1

Cellosaurus cell lines

8 cell lines: 4 cancer cell line, 3 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A2K2	SEES3-1V human H2AFY, clone1	Embryonic stem cell	Male
CVCL_A2K3	SEES3-1V human H2AFY, clone2	Embryonic stem cell	Male
CVCL_A2K4	SEES3-1V human H2AFY, clone3	Embryonic stem cell	Male
CVCL_B3AH	Abcam HEK293T MACROH2A1 KO	Transformed cell line	Female
CVCL_B7Y2	Abcam Raji MACROH2A1 KO	Cancer cell line	Male
CVCL_B9YS	Abcam THP-1 MACROH2A1 KO	Cancer cell line	Male
CVCL_SQ76	HAP1 H2AFY (-) 1	Cancer cell line	Male
CVCL_XP45	HAP1 H2AFY (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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