Transcriptomics,Genomics

Dataset Information

29

MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption


ABSTRACT: The macro domain of the histone variant macroH2A1.1 is an evolutionary conserved ADP ribose-binding module of unknown physiological function. We demonstrate that during myogenic differentiation alternative splicing switches the expression of macroH2A1 from the non-ADP ribose binding to the binding isoform. While differentiation commitment is normal in cells lacking macroH2A1.1, we observe two phenotypes: diminished cell fusion correlating with reduced expression of adhesion and migration genes and reduced mitochondrial capacity. While the integrity of the ADP ribose-binding pocket is dispensable for gene regulation and fusion, it is critical to sustain optimal mitochondrial fatty acid oxidation. Rescue experiments using a pharmacological PARP-1 inhibitor and metabolomics support the idea that loss of macroH2A1.1 leads to PARP-1 activation and accelerated NAD+ consumption. As a consequence, the level of nicotinamide mononucleotide, the key metabolite for mitochondrial NAD+ pool regeneration, is reduced and sirtuins fail to maintain mitochondrial proteins in their hypoacetylated and active form. Our results support the idea that chromatin states containing the histone variant macroH2A1.1 contribute to optimal mitochondrial oxidative capacity by channeling the consumption of NAD+ from the nucleus to mitochondria in a manner largely independent on transcriptional regulation. Overall design: Microarray analysis from 4 biological replicates is performed on C2C12 myotubes at day 4 of differentiation, transfected with either control or macroH2A1.1 siRNAs.

INSTRUMENT(S): Agilent-028005 SurePrint G3 Mouse GE 8x60K Microarray (Feature Number version)

SUBMITTER: Roberto Malinverni  

PROVIDER: GSE70015 | GEO | 2017-08-18

SECONDARY ACCESSION(S): PRJNA287491

REPOSITORIES: GEO

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Publications


Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain w  ...[more]

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