Arginine Methylation by PRMT1 Regulates Muscle Stem Cell Fate

Abstract

Quiescent muscle stem cells (MSCs) become activated in response to skeletal muscle injury to initiate regeneration. Activated MSCs proliferate and differentiate to repair damaged fibers or self-renew to maintain the pool and ensure future regeneration. The balance between self-renewal, proliferation, and differentiation is a tightly regulated process controlled by a genetic cascade involving determinant transcription factors such as Pax7, Myf5, MyoD, and MyoG. Recently, there have been several reports about the role of arginine methylation as a requirement for epigenetically mediated control of muscle regeneration. Here we report that the protein arginine methyltransferase 1 (PRMT1) is expressed in MSCs and that conditional ablation of PRMT1 in MSCs using Pax7CreERT2 causes impairment of muscle regeneration. Importantly, PRMT1-deficient MSCs have enhanced cell proliferation after injury but are unable to terminate the myogenic differentiation program, leading to regeneration failure. We identify the coactivator of Six1, Eya1, as a substrate of PRMT1. We show that PRMT1 methylates Eya1 in vitro and that loss of PRMT1 function in vivo prevents Eya1 methylation. Moreover, we observe that PRMT1-deficient MSCs have reduced expression of Eya1/Six1 target MyoD due to disruption of Eya1 recruitment at the MyoD promoter and subsequent Eya1-mediated coactivation. These findings suggest that arginine methylation by PRMT1 regulates muscle stem cell fate through the Eya1/Six1/MyoD axis.

Platelet releasate promotes skeletal myogenesis by increasing muscle stem cell commitment to differentiation and accelerates muscle regeneration following acute injury

“…IGF1 is known to increase embryonic myoblast proliferation, but Igf1 mRNA levels tend to be higher during myogenic differentiation . Increased mRNA levels of Prmt1 in response to releasate administration are in line with previous data reporting that arginine methylation by Prmt1 regulates muscle stem cell fate and it is important for myoblast fusion . Taken together, these data suggest that the observed effects on myoblast proliferation by platelet releasate may be at least in part mediated by the PDGF and VEGF growth factors.…”

Arginine Methylation: The Coming of Age

“…The absence of PRMT1 in the Pax7-Cre mouse model leads to hypomethylation of Eya1 and subsequent decrease of Eya1 binding to the MyoD promoter. MyoD levels decrease in PRMT1 null muscle stem cells, impairing their differentiation, and increasing their expansion in vivo, ultimately leading to an increase of Pax7-positive cells with disrupted regeneration (Blanc et al, 2016b) (Figure 4).…”

Methylation of the phosphatase‐transcription activator EYA1 by protein arginine methyltransferase 1: mechanistic, functional, and structural studies

“…3A). Indeed, we detected Flag‐tagged EYA1 with ASYM26, an antibody that recognizes asymmetric dimethyl‐arginine (20) in anti‐Flag immuno‐precipitations (Fig. 3 B ).…”

“…A more recent study reported that PRMT1 methylates EYA1 and that loss of PRMT1 function in muscle stem cells leads to reduced transcription of SIX1/EYA1 target genes (such as MyoD and SIX1) due to disruption of EYA1 recruitment at these genes. The authors propose that PRMT1‐mediated methylation of EYA1 may promote EYA1 recruitment at SIX1/EYA1 target genes and subsequent transcriptional activation (20). On the basis of these findings and those of our previous study showing that PRMTs facilitated the recruitment of CBP‐containing transcriptional coactivators during transcriptional activation (21), it is conceivable that PRMT1 may coordinate both the phosphatase and transactivation activities of EYA by arginine methylation.…”

“…Here we identify methylation of EYA1, a substrate of a key enzyme responsible for arginine methylation, PRMT1 (20), on 2 conserved arginine residues (R304 and −06). Mutating the conserved methylated arginine residues in EYA1 abolished its phosphatase activity in vitro , reduced its associations with histones normally triggered by ionizing radiation–induced DNA damage, and disrupted its in vivo function during Drosophila compound eye development.…”