Modulation of Smooth Muscle Gene Expression by Association of Histone Acetyltransferases and Deacetylases with Myocardin

Abstract

Differentiation of smooth muscle cells is accompanied by the transcriptional activation of an array of muscle-specific genes controlled by serum response factor (SRF). Myocardin is a cardiac and smooth muscle-specific expressed transcriptional coactivator of SRF and is sufficient and necessary for smooth muscle gene expression. Here, we show that myocardin induces the acetylation of nucleosomal histones surrounding SRF-binding sites in the control regions of smooth muscle genes. The promyogenic activity of myocardin is enhanced by p300, a histone acetyltransferase that associates with the transcription activation domain of myocardin. Conversely, class II histone deacetylases interact with a domain of myocardin distinct from the p300-binding domain and suppress smooth muscle gene activation by myocardin. These findings point to myocardin as a nexus for positive and negative regulation of smooth muscle gene expression by changes in chromatin acetylation.

ACKNOWLEDGMENTS

We thank Cheol Yong Choi, Tso-Pang Yao, Lishan Su, and Wei Gu for reagents.

E.N.O. was supported by grants from the National Institutes of Health, the Donald W. Reynolds Foundation, and the Texas Advanced Technology Program. D.-Z.W. is a Basil O'Connor Scholar of the March of Dimes Birth Defects Foundation and was supported by grants from the National Institutes of Health, the Muscular Dystrophy Association, and the American Heart Association.