Acetylation of PAX7 controls muscle stem cell self-renewal and differentiation potential in mice

Marie-Claude Sincennes, Caroline E. Brun, Alexander Y. T. Lin, Tabitha Rosembert, David Datzkiw, John Saber, Hong Ming, Yoh-ichi Kawabe and Michael A. Rudnicki ()
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Marie-Claude Sincennes: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Caroline E. Brun: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Alexander Y. T. Lin: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Tabitha Rosembert: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
David Datzkiw: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
John Saber: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Hong Ming: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Yoh-ichi Kawabe: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute
Michael A. Rudnicki: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. Here we report the identification of two acetylation sites on PAX7 that positively regulate its transcriptional activity. Lack of PAX7 acetylation reduces DNA binding, specifically to the homeobox motif. The acetyltransferase MYST1 stimulated by Acetyl-CoA, and the deacetylase SIRT2 stimulated by NAD +, are identified as direct regulators of PAX7 acetylation and asymmetric division in muscle stem cells. Abolishing PAX7 acetylation in mice using CRISPR/Cas9 mutagenesis leads to an expansion of the satellite stem cell pool, reduced numbers of asymmetric stem cell divisions, and increased numbers of oxidative IIA myofibers. Gene expression analysis confirms that lack of PAX7 acetylation preferentially affects the expression of target genes regulated by homeodomain binding motifs. Therefore, PAX7 acetylation status regulates muscle stem cell function and differentiation potential to facilitate metabolic adaptation of muscle tissue.

Date: 2021
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DOI: 10.1038/s41467-021-23577-z

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