Marjanović, Melanija PosavecHurtado-Bagès, Sarah, 1990-Lassi, MaximilianVarela Vázquez, VanesaMalinverni, RobertoDelage, HélèneNavarro, MiriamCorujo García, DavidGuberovic, IvaDouet, JulienGama-Perez, PauGarcía-Roves, Pablo M. (Pablo Miguel)Ahel, IvanLadurner, Andreas G.Yanes, OscarBouvet, PhilippeSuelves Esteban, MònicaTeperino, RaffaelePospisilik, J. AndrewBuschbeck, Marcus2019-02-062019-02-062017-10-091545-9993https://hdl.handle.net/2445/127975Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A.1.1 contains a macrodomain able to bind NAD+ derived metabolites. Here, we report that macroH2A.1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing. Importantly, myotubes lacking macroH2A.1.1 display a defect in mitochondrial respiratory capacity. We find that the metabolite-interacting macrodomain is essential for sustaining optimal mitochondrial function, but dispensable for gene regulation. Through direct binding, macroH2A.1.1 inhibits basal poly-ADP ribose polymerase 1 activity and thus reduces nuclear NAD+ consumption. Consequentially, accumulation of the NAD+ precursor NMN allows the maintenance of mitochondrial NAD+ pools critical for respiration. Our data indicate that macroH2A.1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.9 p.application/pdfeng(c) Marjanovic, Melanija Posavec et al., 2017Nuclis cel·lularsMetabolismeExpressió gènicaHistonesMitocondrisCell nucleiMetabolismGene expressionHistonesMitochondriainfo:eu-repo/semantics/article6738012019-02-06info:eu-repo/semantics/openAccess28991266