Informace o publikaci

Histone variant macroH2A1.1 enhances non-homologous end joining-dependent DNA double-strand-break repair and reprogramming efficiency of human iPSCs

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GIALLONGO Sebastiano ŘEHÁKOVÁ Daniela BIAGINI Tommaso LO RE Oriana RAINA Priyanka LOCHMANOVÁ Gabriela ZDRÁHAL Zbyněk RESNICK Igor PATA Pille PATA Illar MISTRÍK Martin DE MAGALHAES Joao Pedro MAZZA Tommaso KOUTNÁ Irena VINCIGUERRA Manlio

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj STEM CELLS
Citace
www https://academic.oup.com/stmcls/advance-article/doi/10.1093/stmcls/sxab004/6511687
Klíčová slova MacroH2A1.1; DNA damage; cell reprogramming; iPSC
Popis DNA damage repair (DDR) is a safeguard for genome integrity maintenance. Increasing DDR efficiency could increase the yield of induced pluripotent stem cells (iPSC) upon reprogramming from somatic cells. The epigenetic mechanisms governing DDR during iPSC reprogramming are not completely understood. Our goal was to evaluate the splicing isoforms of histone variant macroH2A1, macroH2A1.1 and macroH2A1.2, as potential regulators of DDR during iPSC reprogramming. GFPTrap one step isolation of mtagGFP-macroH2A1.1 or mtagGFP-macroH2A1.2 fusion proteins from overexpressing human cell lines, followed by liquid chromatography tandem mass spectrometry analysis, uncovered macroH2A1.1 exclusive interaction with Poly-ADP Ribose Polymerase 1 (PARP1) and X-ray cross-complementing protein 1 (XRCC1). MacroH2A1.1 overexpression in U2OSGFP reporter cells enhanced specifically Non-Homologous End Joining (NHEJ) repair pathway, while macroH2A1.1 knock-out (KO) mice showed an impaired DDR capacity. The exclusive interaction of macroH2A1.1, but not macroH2A1.2, with PARP1/XRCC1 was confirmed in Human Umbilical Vein Endothelial Cells (HUVEC) undergoing reprogramming into iPSC through episomal vectors. In HUVEC, macroH2A1.1 overexpression activated transcriptional programs that enhanced DDR and reprogramming. Consistently, macroH2A1.1 but not macroH2A1.2 overexpression improved iPSC reprogramming. We propose the macroH2A1 splicing isoform macroH2A1.1 as a promising epigenetic target to improve iPSC genome stability and therapeutic potential.

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