The aim was to characterize PTM of macroH2A1.1 and macro H2A1.2 by LC-MS/MS to facilitate the understanding of their distinct biological functions in health and disease. Next, the interactome of macroH2A1 isoforms was investigated to elucidate whether the two variants could differentially orchestrate genome maintenance and efficiency of reprogramming, i.e., two key aspects of the induced pluripotent stem cell technology (iPSC).