Abstract
PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. We previously found that PAX7 recruits the H3K4 methyltransferases MLL1/2 to epigenetically activate target genes. Here we report that in the absence of Mll1, myoblasts exhibit reduced H3K4me3 at both Pax7 and Myf5 promoters and reduced Pax7 and Myf5 expression. Mll1-deficient myoblasts fail to proliferate but retain their differentiation potential, while deletion of Mll2 had no discernable effect. Re-expression of PAX7 in committed Mll1 cKO myoblasts restored H3K4me3 enrichment at the Myf5 promoter and Myf5 expression. Deletion of Mll1 in satellite cells reduced satellite cell proliferation and self-renewal, and significantly impaired skeletal muscle regeneration. Pax7 expression was unaffected in quiescent satellite cells but was markedly downregulated following satellite cell activation. Therefore, MLL1 is required for PAX7 expression and satellite cell function in vivo. Furthermore, PAX7, but not MLL1, is required for Myf5 transcriptional activation in committed myoblasts.
Highlights
PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation
Chromatin immunoprecipitation (ChIP)-sequencing in primary myoblasts revealed that PAX7 acts as a nodal factor by activating target genes involved in establishing myogenic identity and in stimulating proliferation while inhibiting differentiation[11,12]
We investigated whether MLL1 and MLL2 share the same function in regulating Myf[5] expression using Mll[1] and Mll[2] conditional knockout myoblasts (Mll[1] cKO and Mll[2] cKO) and Mll1:Mll[2] double conditional knockout myoblasts (Mll1:Mll[2] dcKO), derived from RosaCE/+:Mll1fl/fl, RosaCE/+:Mll2fl/fl and RosaCE/+:Mll1fl/fl:Mll2fl/fl mice respectively
Summary
PAX7 is a paired-homeobox transcription factor that specifies the myogenic identity of muscle stem cells and acts as a nodal factor by stimulating proliferation while inhibiting differentiation. Conditional Pax[7] deletion in adult mice strongly impairs the regenerative capacity of skeletal muscle due to proliferation defects and precocious differentiation of satellite cells, confirming the absolute requirement of PAX7 for satellite cell function[9,10]. Chromatin immunoprecipitation (ChIP)-sequencing in primary myoblasts revealed that PAX7 acts as a nodal factor by activating target genes involved in establishing myogenic identity and in stimulating proliferation while inhibiting differentiation[11,12]. The ability of PAX7 to recruit this Trithorax complex to chromatin is regulated by CARM1 and p38γ MAPK14,17 Consistent with these findings, the Myf[5] locus exhibits H3K4me[3] enrichment around the transcription start site (TSS) in quiescent satellite cells as well as in primary myoblasts[12,13,18]. Our data demonstrate that MLL1 is absolutely required for PAX7 expression and satellite cell function
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