Regulation of MicroRNAs by Brahma-related Gene 1 (Brg1) in Smooth Muscle Cells

MicroRNAs are involved in phenotypic switching of smooth muscle cells (SMCs). Brg1-containing SWI/SNF chromatin-remodeling complexes also play an important role in controlling the phenotype of SMCs. We thus determined whether Brg1 influences the transcription of microRNAs in SMCs. Microarray and quantitative RT-PCR analysis of smooth muscle from mice harboring smooth muscle-specific deletion of Brg1 revealed altered expression of several microRNAs, including miRs-143/145 and miR-133. Ablation of Brg1 in SMCs in vitro either by expression of dominant negative Brg1 or Brg1 knock-out attenuated miRs-143/145 expression. Knockdown of serum response factor (SRF) in SMCs significantly reduced the expression levels of miRs-143/145 and miR-133, whereas knockdown of myocardin only attenuated miRs-143/145 expression. Myocardin induced expression of miRs-143/145 and miR-133a and increased SRF binding to these genes in 10T1/2 cells. This myocardin-mediated induction was attenuated by dominant negative Brg1. In Brg1-null SW13 cells, miRs-143/145 were dramatically induced by myocardin only in the presence of Brg1, whereas miR-133 was not induced by myocardin in a Brg1-dependent manner. Chromatin immunoprecipitation assays demonstrated that in the presence of Brg1, myocardin increased SRF binding to both the miRs-143/145 and miR-133a loci. Together, these data suggest a mechanism in which Brg1-containing SWI/SNF complexes are required for myocardin to induce expression of miRs-143/145 in smooth muscle cells. In contrast, miR-133 expression appears to be regulated by Brg1-containing chromatin remodeling complexes in a partially SRF-dependent, although largely myocardin-independent manner. SWI/SNF-mediated chromatin remodeling thus regulates the phenotype of smooth muscle by affecting expression of protein-coding genes and microRNAs.