Recent advances in high-throughput technologies have transformed methodologies employed to study cell-specific epigenomes and the approaches to investigate complex cellular phenotypes. Application of next-generation sequencing technology in the skeletal muscle differentiation field is rapidly extending our knowledge on how chromatin modifications, transcription factors and chromatin regulators orchestrate gene expression pathways guiding myogenesis. Here, we review recent biological insights gained by the application of next-generation sequencing techniques to decode the epigenetic profile and gene regulatory networks underlying skeletal muscle differentiation. 1. Introduction During developmental processes, in response to external cues, changes in chromatin involving activation and repression of transcription factors and chromatin regulators (e.g., chromatin-modifying enzymes) underlie commitment of specific cells to defined lineages. Importantly, transcription factors and chromatin modifiers are also able to alter the cellular expression program to maintain cell identity even upon removal of the initiating differentiation stimuli [1]. During development and in adulthood, cellular identity is established and maintained by finely tuned mechanisms of gene repression and expression, preserved through rounds of cell division. Differentiation processes are achieved by sculpting cell-specific epigenomes, which establish and maintain cellular diversity [2]. Epigenetic information relies on several elements, such as histone modifications, histone variants, nucleosome accessibility, DNA methylation and hydroxymethylation, and nuclear organization. These chromatin states influence access of transcription factors and enzymes to the underlying DNA [1]. 2. Epigenetic Regulators of Myogenesis Myogenic lineage commitment and execution of the terminal differentiation program relies on the activity of the paired-box transcription factors Pax3 and Pax7 and of the muscle regulatory factors (MRFs) MyoD, Myf5, MRF4, and myogenin [3]. Myogenesis is a multistep process, which restricts cell fate and commits cells to become skeletal muscle. During embryonic development, myogenic precursor cells derived from the somites express Pax3 and Pax3/Pax7 and are capable of proliferation and self-renewal [4, 5]. In response to extrinsic signals, Pax3+ cells are committed to myoblasts and undergo terminal myogenic differentiation through the transcriptional network activated by MRFs. During postnatal life, muscle growth relies on satellite cells, which are a subpopulation of
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