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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:921.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

The SWI/SNF Chromatin Remodeling Complex Regulates Myocardin-Induced Smooth Muscle–Specific Gene Expression

Jiliang Zhou; Min Zhang; Hong Fang; Omar El-Mounayri; Jennifer M. Rodenberg; Anthony N. Imbalzano; B. Paul Herring

From the Department of Cellular and Integrative Physiology (J.Z., M.Z., H.F., O.E.-M., J.M.R., B.P.H.), Indiana University School of Medicine, Indianapolis; and the Department of Cell Biology (A.N.I.), University of Massachusetts Medical School, Worcester. Current affiliation for J.Z.: Center for Cardiovascular Sciences, Albany Medical College, NY. Current affiliation for O.E.-M.: Cancer Center, McGill University, Montreal, Qc, Canada. Current affiliation for J.M.R.: Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Tex.

Correspondence to B. Paul Herring, PhD, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202-5120. E-mail pherring{at}iupui.edu

Objective— Regulatory complexes comprising myocardin and serum response factor (SRF) are critical for the transcriptional regulation of many smooth muscle–specific genes. However, little is known about the epigenetic mechanisms that regulate the activity of these complexes. In the current study, we investigated the role of SWI/SNF ATP-dependent chromatin remodeling enzymes in regulating the myogenic activity of myocardin.

Methods and Results— We found that both Brg1 and Brm are required for maintaining expression of several smooth muscle–specific genes in primary cultures of aortic smooth muscle cells. Furthermore, the ability of myocardin to induce expression of smooth muscle–specific genes is abrogated in cells expressing dominant negative Brg1. In SW13 cells, which lack endogenous Brg1 and Brm1, myocardin is unable to induce expression of smooth muscle–specific genes. Whereas, reconstitution of wild-type, or bromodomain mutant forms Brg1 or Brm1, into SW13 cells restored their responsiveness to myocardin. SWI/SNF complexes were found to be required for myocardin to increase SRF binding to the promoters of smooth muscle–specific genes. Brg1 and Brm directly bind to the N terminus of myocardin, in vitro, through their ATPase domains and Brg1 forms a complex with SRF and myocardin in vivo in smooth muscle cells.

Conclusion— These data demonstrate that the ability of myocardin to induce smooth muscle–specific gene expression is dependent on its interaction with SWI/SNF ATP-dependent chromatin remodeling complexes.

We demonstrate that Brg1 and Brm bind directly to myocardin. Brg1 and Brm are required for expression of SRF-dependent smooth muscle–specific genes. Either Brg1 or Brm is required for the myogenic activity of myocardin.

Key Words: Brg1 • Brm • telokin • calponin • SRF