Macroh2a1 is a gene encoding a histone H2A variant. The Macroh2a1 gene generates two alternative splice isoforms, macroH2A1.1 and macroH2A1.2, through alternative splicing [1,2,3,4,5,6,7]. These isoforms contribute to chromatin's additional properties, regulating cell plasticity, proliferation, and participating in processes like pluripotency, tumorigenesis, and the formation of senescence-associated heterochromatic foci (SAHF) in senescent cells [2]. Macroh2a1 also integrates nutritional cues from the extracellular environment to transcriptional programs [2].

Genetically modified mice have provided insights into macroH2A1's function. For example, macroH2A1.1 knock-out (KO) mice showed an impaired DNA damage response (DDR) capacity, indicating macroH2A1.1's role in enhancing nonhomologous end joining (NHEJ)-dependent DNA double-strand-break repair [7]. In myelodysplastic syndromes (MDS), the mH2A1.1 splicing isoform accumulates in mesenchymal stromal cells (MSCs), correlating with the expression of Toll-like receptor 4 (TLR4), affecting the crosstalk between epigenetics, inflammation, and cell metabolism in MDS-MSCs [4].

In summary, Macroh2a1, through its splice isoforms, plays essential roles in multiple biological processes such as cell proliferation, senescence, and DNA damage repair. Studies using KO mouse models have revealed its significance in diseases like MDS and its potential role in DNA repair during induced pluripotent stem cell (iPSC) reprogramming, contributing to our understanding of these disease mechanisms and potential therapeutic targets.