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Nat Commun. 2019 Sep 18;10(1):4256. doi: 10.1038/s41467-019-12086-9.

MLL1 is required for PAX7 expression and satellite cell self-renewal in mice.

Author information

1
Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
2
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
3
Sprott Centre for Stem Cell Research, Ottawa Bioinformatics Core Facility, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
4
Genomics, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden, Tatzberg 47, Dresden, 01307, Germany.
5
Department of Pediatrics and Pharmacology, University of Colorado/Anschutz Medical Campus, Aurora, CO, 80045, USA.
6
Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada. mrudnicki@ohri.ca.
7
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada. mrudnicki@ohri.ca.

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.

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