Regulation of MyoD Post-Transcriptional Modifications

MyoD是肌肉特异性基因表达所必需的转录激活剂。外源性MyoD在许多终末分化细胞系(神经元、脂肪细胞、皮肤细胞、软骨细胞等)中的表达将它们的命运重新定位为骨骼肌表型。此外，MyoD和相关的Myf-5蛋白对动物骨骼肌的形成是必不可少的。为了激活转录，MyoD需要其他相互作用伙伴的帮助，如p300/CBP和PCAF共激活因子。我们以前报道过p300和PCAF是肌肉特异性转录因子MyoD的节点共激活因子。MyoD被PCAF乙酰化，这导致DNA结合和转录活性增加。乙酰化和脱乙酰化处于动态平衡状态，我们的研究确定了组蛋白脱乙酰酶(HDACs)在控制肌肉分化中的作用。为了揭示介导HDACs活性的分子机制和效应器，我们使用小分子抑制骨骼肌细胞中HDACs的酶活性，并进行了微阵列时间谱分析。 此外，由于观察到骨骼肌氧化还原状态随着氧张力和葡萄糖摄取的改变而变化，我们分析了依赖NAD+的脱乙酰酶Sir2在控制肌肉基因表达中的作用。

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.