The role of SWI/SNF in regulating smooth muscle differentiation

Abstract

The myocardin related transcription factors (MRTFs) play a critical role in regulating serum response factor's (SRF) ability to drive smooth muscle differentiation. MRTFs can induce the transcription of smooth muscle‐specific genes in nonmuscle cells through a mechanism involving the induction of SRF binding to the promoters of these genes, within intact chromatin. The goal of our studies is to understand how MRTFs can facilitate SRF binding within an otherwise closed chromatin landscape. We found that MRTFs can recruit SWI/SNF ATP‐dependent chromatin remodeling complexes, to the promoters of smooth muscle‐specific genes thereby permitting high affinity binding of SRF. Expression of dominant negative Brg1 or knockdown of Brg1 attenuated expression of SRF dependent smooth muscle‐specific genes in primary cultures of smooth muscle cells. Immunoprecipitation assays revealed that Brg1, SRF and MRTFs form a complex in vivo and Brg1 directly binds MRTFs in vitro. Dominant negative Brg1 significantly attenuated the ability of MRTFs to increase SRF binding to the promoters of smooth muscle‐specific genes. Mice harboring a smooth muscle‐specific knockout of Brg1 were generated and preliminary analysis of these mice revealed defects in GI development, including a significantly shorter gut with attenuated contractility in Brg1 knockout mice. Supported by DK61130, an AHA fellowship to MZ and an AHA SDG to LZ.