Carm1 Regulates Pax7 Transcriptional Activity through MLL1/2 Recruitment during Asymmetric Satellite Stem Cell Divisions

Abstract

SUMMARY In skeletal muscle, asymmetrically dividing satellite stem cells give rise to committed satellite cells that transcribe the myogenic determination factor Myf5, a Pax7-target gene. We identified the arginine methyltransferase Carm1 as a Pax7 interacting protein and found that Carm1 specifically methylates multiple arginines in the N-terminus of Pax7. Methylated Pax7 directly binds the C-terminal cleavage forms of the trithorax proteins MLL1/2 resulting in the recruitment of the ASH2L:MLL1/2:WDR5:RBBP5 histone H3K4 methyltransferase complex to regulatory enhancers and the proximal promoter of Myf5. Finally, Carm1 is required for the induction of de novo Myf5 transcription following asymmetric satellite stem cell divisions. We defined the C-terminal MLL region as a novel reader domain for the recognition of arginine methylated proteins such as Pax7. Thus, arginine methylation of Pax7 by Carm1 functions as a molecular switch controlling the epigenetic induction of Myf5 during satellite stem cell asymmetric division and entry into the myogenic program.

Protein arginine methyltransferase expression, localization, and activity during disuse-induced skeletal muscle plasticity

“…Intracellular signaling molecules such as peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α), calcineurin (CN), p38 mitogen-activated protein kinase (p38), AMP-activated protein kinase (AMPK), silent mating type information regulator 2 homologue 1 (SIRT1), PPARβ and tumor suppressor protein p53 play a role in remodelling skeletal muscle toward a slower, more oxidative phenotype (16,18,19,20,21,22,23,24,25). In contrast, receptor interacting protein 140 (RIP140), E2F transcription factor 1 (E2F1), nuclear receptor corepressor 1 (NCoR1), and Baf60c have been shown to promote faster, more glycolytic characteristics (26,27,28,29,32). Thus, numerous molecules participate in the coordinated expression of morphological, biochemical and functional characteristics that define, and remodel, skeletal muscle phenotype (Fig.…”

Prmt7 Deficiency Causes Reduced Skeletal Muscle Oxidative Metabolism and Age-Related Obesity

“…Prmt4 and Prmt5 have been implicated in promotion of myoblast differentiation through interaction with Mef2c or MyoD, respectively (36,37). Recent studies with muscle stem cell-specific knockout mouse models have suggested that Prmt4 and Prmt5 play critical roles in control of muscle stem cell functions during muscle regeneration (38,39). In this study, we characterized the role of Prmt7 in skeletal muscle metabolism by using Prmt7-deficient mouse models.…”

G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy

“…However, SCs are still heterogenic, and among the distinct differentiation stages, the satellite stem cell population must be maintained to preserve their stemness, that is, long-term self-renewal and differentiation abilities. Accumulating data indicate that SCs maintain their population by asymmetric cell division [1][2][3][4] . The different differentiation stages of SCs are distinguishable by the expression of specific markers such as PAX7 and MYOD; PAX7 þ /MYOD À cells are quiescent, PAX7 þ /MYOD þ cells are activated and PAX7 À /MYOD þ cells are differentiating.…”