Epigenetic Regulation of Skeletal Muscle Development and Differentiation

Abstract

Skeletal muscle cells have served as a paradigm for understanding mechanisms leading to cellular differentiation. Formation of skeletal muscle involves a series of steps in which cells are committed towards the myogenic lineage, undergo expansion to give rise to myoblasts that differentiate into multinucleated myotubes, and mature to form adult muscle fibers. The commitment, proliferation, and differentiation of progenitor cells involve both genetic and epigenetic changes that culminate in alterations in gene expression. Members of the Myogenic regulatory factor (MRF), as well as the Myocyte Enhancer Factor (MEF2) families control distinct steps of skeletal muscle proliferation and differentiation. In addition, -growing evidence indicates that chromatin modifying enzymes and remodeling complexes epigenetically reprogram muscle promoters at various stages that preclude or promote MRF and MEF2 activites. Among these, histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs) and SWI/SNF complexes alter chromatin structure through post-translational modifications to impact MRF and MEF2 activities. With such new and emerging knowledge, we are beginning to develop a true molecular understanding of the mechanisms by which skeletal muscle development and differentiation is regulated. Elucidation of the mechanisms by which epigenetic regulators control myogenesis will likely provide a new foundation for the development of novel therapeutic drugs for muscle dystrophies, ageing-related regeneration defects that occur due to altered proliferation and differentiation, and other malignancies.

Genome‐wide association between Six4, MyoD, and the histone demethylase Utx during myogenesis

“…A large number of TFs have been shown to be expressed and to carry out important functions during adult muscle regeneration after injury (reviewed in refs. [70][71][72]. Although Six4 has been studied in the context of embryonic myogenesis, no role has been ascribed to this homeodomain TF in muscle regeneration.…”

Are cultured human myotubes far from home?

“…Epigenetic regulation of skeletal muscle stem cells and skeletal muscle differentiation are well known (see e.g. (Bharathy, et al, 2012, Sousa-Victor, et al, 2011). Exercise (Barres, et al, 2012, Nitert, et al, 2012, diet (Jacobsen, et al, 2012) and family history of type 2 diabetes (Nitert, et al, 2012) are all described to influence DNA methylation in human skeletal muscle, traits that may follow the isolated satellite cells into cultured myotubes.…”

p38α MAPK disables KMT1A-mediated repression of myogenic differentiation program

“…Accordingly, switching myoblasts from proliferation into differentiation is underpinned by specific epigenetic events to transition myogenic loci from a transcriptionally repressive to activating state. This is caused by chromatin-associated activities, ranging from covalent modification of histones and myogenic regulatory factors to chromatin remodeling [4, 10, 14, 20, 21]. In growing myoblasts, MyoD-bound muscle-specific genes are generally epigenetically marked for transcriptional repression through trimethylation of histone H3 at Lys 9 (H3K9me3) and/or Lys 27 (H3K27me3) on promoter/enhancer regions to control their temporal expression [21–25].…”

“…An essential step in establishing active transcription at myogenic loci is the temporal recruitment of specific chromatin modifiers that promote MyoD-orchestrated myogenic gene expression and differentiation [10, 14, 20]. At the onset of myoblast differentiation, predominant signaling pathways such as p38α MAPK and PI3/AKT play a major role in transitioning from a transcriptionally repressive to permissive chromatin environment for MyoD-initiated myogenic differentiation program [28–32].…”