RNA-binding proteins and gene regulation in myogenesis

Abstract

Skeletal muscle development, repair and function are dependent on highly coordinated expression of many genes. RNA-binding proteins are crucial determinants of gene expression in the health and disease of various tissues, including skeletal muscle. A variety of RNA-binding proteins are associated with a transcript during its life cycle and define the lifetime, cellular localization, processing and rate at which that transcript is translated and ultimately degraded. The focus of this review is to highlight the roles of the best-characterized RNA-binding proteins in muscle, including HuR, KSRP, CUGBP1, PABPN1, Lin-28 and TTP. Recent studies indicate key functions for these RNA-binding proteins in different aspects of muscle physiology. Understanding the role of specific RNA-binding proteins in skeletal muscle will provide insights not only into basic mechanisms regulating gene expression in muscle, but also into the etiology and pathology of muscle disease.

Figure 1. Main regulatory steps during myogenesis in skeletal muscle

Myogenesis occurs during embryonic development and adult muscle regeneration. Schematic shows the main cellular transitions that occur during myogenesis and the key regulatory proteins (right) that control these transitions. In the embryo, precursor cells in the somites become determined for the myogenic lineage and proliferate to give rise to myoblasts. The transcription factors MyoD and Myf5 are critical for determination. In the adult, precursor cells called satellite cells begin to proliferate in response to injury and give rise to myoblasts. MyoD and Myf5 also regulate the proliferation of myoblasts in both embryos and adults. During later stages of myogenesis, myoblasts differentiate, withdraw from the cell cycle and fuse to form myofibers which grow in size. Transcription factors such as myogenin, MEF2 and MRF4 and the cell cycle inhibitor p21 play key roles during these later stages of myogenesis.

Figure 2. Post-transcriptional control of RNA metabolism occurs at multiple steps

Post-transcriptional regulation can occur throughout the RNA life cycle, from processing and nuclear export to translation and ultimately degradation. These processes are regulated by the dynamic association of RNA-binding proteins (RBPs, showed in colored shapes) with mRNA, which define a transcript’s lifetime, cellular localization, editing, polyadenylation and rates of translation and decay, ultimately determining the levels of protein produced.

Figure 3. Roles of selected RNA-binding proteins in myogenesis

Shown schematically are the RNA-binding proteins discussed in this review together with their respective mRNA targets in skeletal muscle. For each RNA-binding protein, the cis-element within the mRNA to which it binds is shown. These RNA-binding proteins mainly regulate proliferation or differentiation of myoblasts. See text for details.