New insights into the epigenetic control of satellite cells

Abstract

Epigenetics finely tunes gene expression at a functional level without modifying the DNA sequence, thereby contributing to the complexity of genomic regulation. Satellite cells (SCs) are adult muscle stem cells that are important for skeletal post-natal muscle growth, homeostasis and repair. The understanding of the epigenome of SCs at different stages and of the multiple layers of the post-transcriptional regulation of gene expression is constantly expanding. Dynamic interactions between different epigenetic mechanisms regulate the appropriate timing of muscle-specific gene expression and influence the lineage fate of SCs. In this review, we report and discuss the recent literature about the epigenetic control of SCs during the myogenic process from activation to proliferation and from their commitment to a muscle cell fate to their differentiation and fusion to myotubes. We describe how the coordinated activities of the histone methyltransferase families Polycomb group (PcG), which represses the expression of developmentally regulated genes, and Trithorax group, which antagonizes the repressive activity of the PcG, regulate myogenesis by restricting gene expression in a time-dependent manner during each step of the process. We discuss how histone acetylation and deacetylation occurs in specific loci throughout SC differentiation to enable the time-dependent transcription of specific genes. Moreover, we describe the multiple roles of microRNA, an additional epigenetic mechanism, in regulating gene expression in SCs, by repressing or enhancing gene transcription or translation during each step of myogenesis. The importance of these epigenetic pathways in modulating SC activation and differentiation renders them as promising targets for disease interventions. Understanding the most recent findings regarding the epigenetic mechanisms that regulate SC behavior is useful from the perspective of pharmacological manipulation for improving muscle regeneration and for promoting muscle homeostasis under pathological conditions.

Keywords: Histone methylation, Histone acetylation, Muscle stem cells, Adult stem cells, Noncoding RNAs, Satellite cell activation, Satellite cell differentiation, Satellite cell quiescence

Core tip: Skeletal muscle needs to efficiently respond to internal and external stimuli, and satellite cells (SCs), the stem cells of muscle, play key roles in the preservation of muscle mass under both physiological and pathological conditions. Epigenetic pathways participate in coordinating the precise time-dependent expression of different subsets of myogenic genes in SCs. Thus, these pathways represent promising targets for therapeutic interventions. In this review, we focus on the epigenetic changes mediated by histone modifications - methylation or acetylation - and by noncoding mRNAs throughout SC differentiation.