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.
Highlights
Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear
To determine the role of PAX7 acetylation, the two lysine residues were substituted with arginine by site-directed mutagenesis
Our results suggest that MYST1 and SIRT2 together control the level of PAX7 acetylation, which is required for satellite cell self-renewal
Summary
Muscle stem cell function has been suggested to be regulated by Acetyl-CoA and NAD+ availability, but the mechanisms remain unclear. 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. PAX7 methylation by CARM1 during asymmetric division has been shown to promote PAX7 interaction with MLL1/2 to activate Myf[5] transcription in the committed daughter cell[12,13,14,15]. This highlights the importance of post-translational regulation of PAX7 function. We identify two lysine acetylation sites that modulate PAX7 transcriptional activity in satellite cells We demonstrate that these acetylation events induce preferential binding to homeodomain motifs, affecting PAX7 gene targeting. Our findings provide important insight into the mechanistic control of satellite stem cell self-renewal through the regulation of posttranslational modifications on PAX7, and elucidate how metabolic cues influence stem cell function
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