Regulation of MyoD Post-Transcriptional Modifications

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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 adn others) redirect 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 activate transcription, MyoD requires the assistance of other interacting partners such as the p300/CBP and PCAf coactivators. We have previously reported that p300 and PCAF are nodal coactivators of the muscle specific transcription factor MyoD. MyoD is acetylated by PCAF and this results in an increased DNA-binding and transcriptional activity. Acetylation and deacetylation are in a dynamic equilibrium and our studies have identified a role for the histone deacetylases (HDACs) in controlling muscle differentiation. To uncover the molecular mechanisms and the effectors that mediate the HDACs activity, we have used small molecules to inhibit the enzymatic activity of HDACs in skeletal muscle cells and performed microarray temporal profiling. Furthermore, prompted by the observation that the redox state fluctuates in skeletal muscle in response to modification of oxygen tension and glucose uptake, we have analyzed the role of the NAD+-dependent deacetylase Sir2 in controlling muscle gene expression.