SWI/SNF Complexes Containing Brahma or Brahma-Related Gene 1 Play Distinct Roles in Smooth Muscle Development

Abstract

SWI/SNF ATP-dependent chromatin-remodeling complexes containing either Brahma-related gene 1 (Brg1) or Brahma (Brm) play important roles in mammalian development. In this study we examined the roles of Brg1 and Brm in smooth muscle development, in vivo, through generation and analysis of mice harboring a smooth muscle-specific knockout of Brg1 on wild-type and Brm null backgrounds. Knockout of Brg1 from smooth muscle in Brg1 flox/flox mice expressing Cre recombinase under the control of the smooth muscle myosin heavy-chain promoter resulted in cardiopulmonary defects, including patent ductus arteriosus, in 30 to 40% of the mice. Surviving knockout mice exhibited decreased expression of smooth muscle-specific contractile proteins in the gastrointestinal tract, impaired contractility, shortened intestines, disorganized smooth muscle cells, and an increase in apoptosis of intestinal smooth muscle cells. Although Brm knockout mice had normal intestinal structure and function, knockout of Brg1 on a Brm null background exacerbated the effects of knockout of Brg1 alone, resulting in an increase in neonatal lethality. These data show that Brg1 and Brm play critical roles in regulating development of smooth muscle and that Brg1 has specific functions within vascular and gastrointestinal smooth muscle that cannot be performed by Brm.The SWI/SNF complex is perhaps the best-characterized mammalian ATP-dependent chromatin-remodeling complex (8). It is comprised of 7 to 11 components, which assemble into distinct complexes containing either Brahma-related gene 1 (Brg1) or Brahma (Brm) ATPase subunits. Brg1 and Brm are ubiquitously expressed in almost all tissues. Studies have suggested that Brg1 and Brm can have either redundant or distinct roles in regulating gene expression. For example, although Brg1 but not Brm has been shown to interact with Crp2 and subsequently induce expression of smooth muscle (SM)-specific genes (4), either Brg1 or Brm has been shown to be sufficient to support the smooth muscle myogenic activity of the myocardin family of activators in SW13 cells (33,34). Data from knockout mice suggest that Brg1-and Brm-containing SWI/SNF complexes are functionally distinct in vivo. Brg1 knockout mice die early in embryonic development during the periimplantation stage (1), while global Brm knockout mice develop normally. On a 129/sv background but not a mixed 129/sv ϫ C57BL/6 background, adult Brm knockout mice exhibited a higher body weight than wild-type (WT) littermates (24).To circumvent the embryonic lethality observed in Brg1 knockout mice, several groups have generated and analyzed tissue-specific Brg1 knockout mice. These studies have revealed unique roles for Brg1-containing SWI/SNF complexes in development of many tissues (5, 11-13, 16, 20, 26). However, few of these studies have determined if Brm also contributes to these developmental pathways. One study combined a tissuespecific Brg1 knockout with a global Brm knockout to show that further loss of Brm did not exacerbate the erythropoietic or endothel...

Brahma is required for cell cycle arrest and late muscle gene expression during skeletal myogenesis

“…Both Brg1 and Brm are also known to interact with and stimulate the activity of several transcription factors, including the glucocorticoid receptor and C/EBP [16,17]. Other studies have suggested a functional redundancy between Brm and Brg1 [18][19][20][21].…”

“…Brg1 binds to zinc finger protein through a unique N-terminal domain not present in Brm, while Brm interacts with two ankyrin-repeats proteins that are crucial in the Notch signal transduction [30]. More recently, studies have investigated the individual roles of Brg1 and Brm in various cellular processes, revealing again individual, cooperating, and redundant activities of these two proteins depending on the cell type and the specific context [18][19][20][21].…”

97 BRG1 Plays an Essential Role in Development and Homeostasis of the Duodenum Through Regulation of Notch Signaling

“…Brg1 is required for inhibition of apoptosis in the development of various cell types and organs, including neurons (Li et al, 2013), smooth muscle (Zhang et al, 2011) and blood cells (Griffin et al, 2008); consequently, knockout of Brg1 increases the rate of apoptosis in these tissues. Our data showing that elevated apoptosis was reversed by Notch1 ICD overexpression in VBN mice demonstrate that marked downregulation of Notch signaling is responsible for increased apoptosis in Brg1-deficient duodenum.…”

“…Brg1 is involved in apoptosis and cell proliferation during organ development (Griffin et al, 2008;Hang et al, 2010;Li et al, 2013;Seo et al, 2005;Zhang et al, 2011). Therefore, we next investigated whether the abnormal villous structure in Brg1-deficient duodenum was associated with changes in apoptosis or cell proliferation.…”

“…Brg1-null mice die during the peri-implantation stage, whereas Brm-null mice develop normally (Bultman et al, 2000;Reyes et al, 1998). Recent studies showed that Brg1 is essential for development or homeostasis of various organs and cell types, including heart (Hang et al, 2010;Takeuchi et al, 2011), vasculature (Davis et al, 2013;Griffin et al, 2008Griffin et al, , 2011, ureter (Weiss et al, 2013), smooth muscle (Zhang et al, 2011) and neurons (Li et al, 2013;Matsumoto et al, 2006;Seo et al, 2005). In the intestine, Brg1 is essential for maintenance of intestinal stem cells (Holik et al, 2013).…”