Control of Adult and Aging Myogenesis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

The specification of skeletal muscle cells, starting from totipotent stem cells, lies at the core of skeletal myogenesis. During this process, the genome of the progenitor muscle cells is modified to ensure that stable, if not irreversible, distinctions are made between genes not to be expressed and genes whose expression is or will be required. MyoD is a transcriptional activator required for muscle-specific gene expression. Expression of exogenous MyoD in numerous terminally differentiated cell lineages (neurons, adipocytes, skin cells, chondrocytes, and others) redirects their fates towards the skeletal muscle phenotype. Furthermore, MyoD and the related Myf-5 protein is essential for the formation of skeletal muscles in the animal. In order to regulate transcription, MyoD recruits chromatin-and histone-modifying enzymes. Specification and maintenance of committed, yet undifferentiated, muscle precursors are the result of a fine balance between gene activation and repression. Genes to be expressed in terminally differentiated cells are actively repressed in muscle precursors. Ezh2, the subunit conferring methyltransferase activity to the Polycomb Repressive Complex 2 (PRC2), occupies and methylates histones located at regulatory regions of muscle-specific genes not expressed in muscle precursors. Once differentiation ensues, Ezh2 binding is lost and histone methylation is erased, resulting in transcriptional activation. Several long non-coding RNAs (lncRNAs) have been implicated in regulating myogenesis both in cis and in trans. It will be of particular interest to identify the mechanisms through which lncRNAs control transcription in trans because of the potential to target gene expression by modulating enhancer function.Epigenetic regulators and lcRNAs become dysregulated in aging muscle stem cells. With the aim of contributing to a better understanding of the mechanisms that regulate gene expression in physiological (adult and aging) and pathological conditions, we will continue to identify and functionally characterize molecules that cause histone and chromatin modifications and regulate proliferation, differentiation, and regeneration of skeletal muscle cells. Aging is associated with epigenetic, transcriptional, and metabolic changes leading to impaired muscle homeostasis and regeneration. By comparing gene expression profiles, chromatin accessibility, epigenetic marks, and metabolites in adult and aging muscle stem cells and myofibers, we will develop atlases which will allow us to identify specific modifications occurring in aged muscles.