Department of Cardiology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
J Biol Chem. 2012 Nov 9;287(46):38495-504. doi: 10.1074/jbc.M112.353649. Epub 2012 Sep 23.
Myocardin belongs to the SAF-A/B, Acinus, PIAS (SAP) domain family of transcription factors and is specifically expressed in cardiac and smooth muscle. Myocardin functions as a transcriptional coactivator of SRF and is sufficient and necessary for smooth muscle gene expression. We have previously found that myocardin induces the acetylation of nucleosomal histones surrounding SRF-binding sites in the control regions of cardiac and smooth muscle genes through recruiting chromatin-modifying enzyme p300, yet no studies have determined whether myocardin itself is similarly modified. In this study, we show that myocardin is a direct target for p300-mediated acetylation. p300 acetylates lysine residues at the N terminus of the myocardin protein. Interestingly, a direct interaction between p300 and myocardin, which is mediated by the C terminus of myocardin, is required for the acetylation event. Acetylation of myocardin by p300 enhances the association of myocardin and SRF as well as the formation of the myocardin-SRF-CArG box ternary complex. Conversely, acetylation of myocardin decreases the binding of histone deacetylase 5 (HDAC5) to myocardin. Acetylation of myocardin is required for myocardin to activate smooth muscle genes. Our study demonstrates that acetylation plays a key role in modulating myocardin function in controlling cardiac and smooth muscle gene expression.
肌球蛋白属于 SAF-A/B、肌球蛋白、PIAS（SAP）结构域转录因子家族，特异性表达于心肌和平滑肌。肌球蛋白作为 SRF 的转录共激活因子发挥作用，对于平滑肌基因表达是充分且必需的。我们之前发现肌球蛋白通过募集染色质修饰酶 p300 诱导围绕心脏和平滑肌基因的调控区中 SRF 结合位点的核小体组蛋白的乙酰化，然而，尚未有研究确定肌球蛋白本身是否也存在类似的修饰。在本研究中，我们表明肌球蛋白是 p300 介导的乙酰化的直接靶标。p300 乙酰化肌球蛋白蛋白的 N 端赖氨酸残基。有趣的是，p300 与肌球蛋白之间的直接相互作用，是由肌球蛋白的 C 端介导的，对于乙酰化事件是必需的。p300 对肌球蛋白的乙酰化增强了肌球蛋白和 SRF 的结合以及肌球蛋白-SRF-CArG 框三元复合物的形成。相反，组蛋白去乙酰化酶 5（HDAC5）与肌球蛋白的结合减少。肌球蛋白的乙酰化对于肌球蛋白激活平滑肌基因是必需的。我们的研究表明，乙酰化在调节肌球蛋白在控制心脏和平滑肌基因表达中的功能方面发挥着关键作用。
