MACROH2A1: A Key Epigenetic Regulator and Tumor Suppressor
Comprehensive genomic and functional analysis of the MACROH2A1 gene, encoding a histone variant involved in chromatin regulation, X-chromosome inactivation, and cancer.
Gene Information Card
| Symbol | MACROH2A1 |
|---|---|
| Full Name | macroH2A.1 histone |
| Gene Type | protein-coding |
| Chromosomal Location | 5q31.2 |
| NCBI Gene ID | 9555 ncbi.nlm.nih.gov/gene/9555 |
| Ensembl ID | ENSG00000113522 |
| UniProt ID | O75367 |
| OMIM ID | 602715 |
| HGNC ID | 4744 |
| Aliases | H2AFY, macroH2A1.1, macroH2A1.2, mH2A1, H2A.y, H2A/y |
Description
MACROH2A1 (macroH2A.1 histone) encodes a variant of histone H2A that contains a large macro domain. This histone variant replaces conventional H2A in nucleosomes and is enriched on the inactive X chromosome in females, playing a critical role in X-chromosome inactivation. MACROH2A1 also functions as a transcriptional repressor by promoting a compact chromatin state and is implicated in cellular senescence, DNA repair, and cancer suppression. Alternative splicing produces two major isoforms: macroH2A1.1 and macroH2A1.2, which differ in their macro domain and NAD+ metabolite binding properties.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Breast Cancer | Loss of MACROH2A1 expression correlates with poor prognosis; promotes epithelial-mesenchymal transition and metastasis | PMID: 25944712; COSMIC |
| Colorectal Cancer | Reduced MACROH2A1 levels associated with tumor progression and worse survival; acts as a tumor suppressor | PMID: 27058617; COSMIC |
| Melanoma | MACROH2A1 loss enhances melanoma cell proliferation and invasion; epigenetic silencing observed | PMID: 25944712; COSMIC |
| Lung Cancer | Downregulation of MACROH2A1 linked to aggressive tumor phenotypes and poor outcome | PMID: 27058617; COSMIC |
| Hepatocellular Carcinoma | MACROH2A1 expression is reduced in HCC; re-expression suppresses tumor growth | PMID: 25944712; COSMIC |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Testis | 15.2 | Medium |
| Spleen | 12.8 | Medium |
| Lung | 10.5 | Medium |
| Liver | 9.1 | Low |
| Brain | 7.3 | Low |
| Heart | 6.9 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa | 18.4 | Cervical cancer cell line; moderate expression |
| A549 | 14.7 | Lung adenocarcinoma cell line |
| MCF7 | 12.3 | Breast cancer cell line |
| HEK293 | 11.0 | Embryonic kidney cell line |
| K562 | 9.8 | Leukemia cell line |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.1A>G (p.Met1?) | missense | <0.01% | Loss of start codon; predicted loss of function |
| c.214C>T (p.Arg72Trp) | missense | <0.01% | Substitution in macro domain; may affect NAD+ binding |
| c.523G>A (p.Gly175Ser) | missense | <0.01% | Located in histone fold domain; uncertain significance |
| c.742_743del (p.Leu248fs) | frameshift | <0.01% | Frameshift leading to premature stop; loss of function |
Mutation functional classification
Loss of Function (LOF)
Frameshift and nonsense mutations that truncate the protein, as well as missense mutations in critical domains (e.g., macro domain, histone fold), are predicted to impair chromatin binding and transcriptional repression, contributing to tumor progression.
Gain of Function (GOF)
No gain-of-function mutations have been reported for MACROH2A1 in the literature or curated databases.
Dominant Negative (DN)
No dominant-negative mutations have been characterized; however, missense variants in the macro domain could theoretically interfere with wild-type function by competing for binding sites.
View complete mutation data：
Gene Ontology (GO)
| • chromatin binding | • nucleosome assembly |
| • negative regulation of transcription by RNA polymerase II | • X-chromosome inactivation |
| • DNA repair | • cellular senescence |
| • NAD+ nucleosidase activity |
Pathways
• Chromatin organization
• X-inactivation
• Cellular senescence
• DNA damage response
Protein Summary
MACROH2A1 is a histone H2A variant characterized by a large C-terminal macro domain that binds NAD+ metabolites. It replaces conventional H2A in a subset of nucleosomes, promoting a more compact chromatin structure and transcriptional silencing. The protein is enriched on the inactive X chromosome in females and is involved in X-chromosome inactivation. MACROH2A1 also plays roles in DNA repair, cellular senescence, and tumor suppression. Its two major splice isoforms, macroH2A1.1 and macroH2A1.2, differ in their ability to bind NAD+ and regulate gene expression. Loss of MACROH2A1 expression is observed in multiple cancers and correlates with poor prognosis.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| MACROH2A1 Knockout HEK293 Cell Line | EDJ-KQ2482 | Human | 9555 | Details Get a Quote |
| MACROH2A1 Knockout A-549 Cell Line | EDJ-KQ23056 | Human | 9555 | Details Get a Quote |
| MACROH2A1 Knockout HCT 116 Cell Line | EDJ-KQ23057 | Human | 9555 | Details Get a Quote |
| MACROH2A1 Knockout HeLa Cell Line | EDJ-KQ23058 | Human | 9555 | Details Get a Quote |
