Muscle Stem Cell Self Renewal is Regulated by Acetylation of PAX7

Abstract

The transcription factor PAX7 is a critical regulator of satellite cell survival, self-renewal and proliferation. PAX7 protein is regulated by different post-translational modifications that affect its transcriptional activity, and consequently, influence muscle regeneration. Here, we report two novel acetylation sites on the PAX7 protein, which regulate its transcriptional activity and chromatin binding. Abolishing PAX7 acetylation using CRISPR/Cas9 mutant mice impairs muscle regeneration and leads to progressive satellite cell exhaustion. We identified molecular regulators of PAX7 acetylation, the acetyltransferase MYST1 as well as with the deacetylase SIRT2, both of which control PAX7 acetylation levels and PAX7 target gene expression in myoblasts. MYST1 and SIRT2 are also important players in regulating the balance between satellite stem cell symmetric versus asymmetric division, therefore controlling satellite cell expansion, self-renewal and commitment. Our data demonstrate that acetylation levels regulate PAX7 transcriptional activity and function in satellite cells.

Keywords: Skeletal muscle, Satellite cell, muscle stem cell, Pax7, Myst1, Sirt2, Acetylation, Transcriptional activation, Asymmetric cell division, regeneration, Metabolism