Core histone macro-H2A.1 (MACROH2A1)

Core histone macro-H2A.1 (MACROH2A1) is a histone variant distinguished by its tripartite structure: a histone fold domain (similar to canonical H2A), an intrinsically disordered linker, and a large C-terminal macrodomain. Alternative splicing creates two main isoforms, macroH2A1.1 and macroH2A1.2, which have opposing biological functions due to differences in macrodomain ligand binding (macroH2A1.1 binds ADP-ribose, macroH2A1.2 does not). MacroH2A1 is involved in chromatin compaction, transcriptional repression, nuclear organization, and the regulation of cellular metabolism, notably through direct inhibition of PARP1, affecting NAD+ metabolism and DNA repair. It is highly conserved and enriched at transcriptionally silent chromatin domains such as the inactive X chromosome in female mammals, acting as an epigenetic barrier to pluripotency and tumor progression. Loss of macroH2A1 is associated with increased chromatin plasticity and tumor progression, while its presence limits chromatin remodeling, transcriptional noise, and promotes robust gene expression programs.

Other names

H2AFYHistone macroH2A1mH2A1H2A/ymacroH2A1.2Histone H2A.yMedulloblastoma antigen MU-MB-50.205H2AF12MMACROH2A1.1H2A histone family member Yhistone macroH2A1.1histone macroH2A1.2

MacroH2A1.1 binds to ADP-ribose and inhibits PARP1 enzymatic activity, thereby affecting NAD+ metabolism, DNA repair, and gene regulation. It recruits histone deacetylases (HDACs) and modulates the acetylation status of chromatin, contributing to transcriptional repression. Its incorporation into chromatin alters nucleosome structure, making chromatin less accessible and more refractory to remodeling.