Promoter-specific restriction of MyoD binding and feed-forward regulation cooperate to produce a multi-staged transcriptional program during skeletal myogenesis.

다국어 초록 (Multilingual Abstract)

The generation of multiple, highly specialized cell types in a regulated and reproducible manner is a challenge that all multicellular organisms face during development, yet the molecular mechanisms that pattern gene expression remain largely unknown. Coordinated gene expression in skeletal myogenesis is initiated by the muscle specific transcription factor MyoD. Here we show that an inducible MyoD-Estrogen Receptor chimeric protein, when expressed in mouse fibroblasts, generates a complex, multi-staged transcriptional response. MyoD recruitment in vivo is regulated in a promoter-specific manner, with immediate binding to early-stage genes, and binding delayed until the second day of differentiation at late-stage genes, suggesting that regulated MyoD recruitment is important in determining the timing of gene activation. In addition, MyoD regulates the expression of specific Mef2 isoforms and the activity of the p38 MAPK pathway. Subsequently, Mef2 and p38 cooperate with MyoD to regulate RNA Polymerase II recruitment and progression at late-stage genes, establishing a temporal pattern of gene expression. Thereby, MyoD directly activates genes expressed throughout the program of muscle differentiation and uses a feed-forward regulatory circuit to generate a multi-stage transcriptional program.