Differential modulation of cell cycle progression distinguishes members of the myogenic regulatory factor family of transcription factors

The muscle-specific basic helix-loop-helix proteins MyoD, Myf5, myogenin (Myog) and MRF4 constitute the myogenic regulatory factor (MRF) family of transcription factors that drive muscle gene expression during myogenesis. Having evolved from a single ancestral gene, the spatial and temporal specificity of expression for each family member has been used to define a hierarchical relationship between the four MRFs. Molecular characterization of two of the MRFs (MyoD and Myog) suggests an important distinction between these factors, whereby MyoD establishes an open chromatin structure at muscle-specific genes, whereas Myog drives high levels of transcription of genes within this open chromatin state. Furthermore, recent data have provided an additional distinction between MRF function with respect to cell cycle regulation. Indeed, MyoD has been shown to directly activate genes involved in cell cycle progression, leading to myoblast proliferation. In contrast, Myog has antiproliferative activity through the activation of genes that shut down the cell proliferation machinery, leading to cell cycle exit and myoblast differentiation. Although the transcriptional activities of MyoD and Myog synergize to drive muscle differentiation, it is the expression of Myog that sets in motion a gene expression program that constitutes a 'point of no return', leading to cell cycle exit. In this review, we compare and contrast the current literature with respect to MRF function, with a particular emphasis on the differential role of MRFs in modulating the cell cycle.