BRG-1 Is Recruited to Estrogen-Responsive Promoters and Cooperates with Factors Involved in Histone Acetylation

Abstract

Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER-BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.Precise regulation of gene expression underlies the ability of a cell to control growth and to acquire and execute physiologic functions. Broad arrays of cellular signals are transduced to the nucleus, where many act on transcription factors. These diverse regulatory signals must be integrated into smaller subsets that can be transmitted to targets that modulate the basal transcription machinery. One such target is chromatin, and there exists abundant evidence that the structure and chemical composition of chromatin directly affect gene expression (35). The primary structural components of chromatin, the histones, are enzymatically acetylated, and this acetylation results in a reduced affinity for DNA and enhanced binding affinity for certain transcriptional coregulators (7). Chromatin structure is also altered via the ATP-dependent disruption of nucleosomes by large multiprotein chromatin remodeling complexes (3). One such complex, the Swi/Snf complex, is well conserved through evolution and functions as a global regulator of transcription (37). These and other mechanisms account for the link between the chemical and structural modification of chromatin and transcriptional activation by members of the nuclear receptor superfamily.The nuclear receptor superfamily ...

Mutational Analysis of Prohibitin - A Highly Conserved Gene in Indian Female Breast Cancer Cases

“…Brg1 has been reported to be connected with the activation of ERα-mediated transcription (DiRenzo et al, 2000) and further it was found that prohibitin interacts with Brg1/Brm and represses ERα mediated transcription after the binding of estrogen antagonist to the ERα, by the mechanism requiring both Brg1 and Brm (Zhang et al, 2007). Research has also shown that the depletion of prohibitin using siRNA prevented tamoxifen-induced cell cycle arrest from the tamoxifen-sensitive breast cancer cells (Wang et al, 2004) exploring a powerful connection between Estrogen and Prohibitin.…”

Members of the hSWI/SNF chromatin remodeling complex associate with and are phosphorylated by protein kinase B/Akt

“…Chromatin immunoprecipitation experiments have demonstrated the presence of hSWI/SNF components on the promoters of IFNgand IFNa-inducible genes, as well as on the IFNb promoter (Agalioti et al, 2000;Huang et al, 2002;Liu et al, 2002;Pattenden et al, 2002;Cui et al, 2004). hSWI/SNF is also present on the CD44 and E-cadherin promoters (Banine et al, 2005;Gresh et al, 2005), on the promoters for myogenin and muscle creatine kinase (Simone et al, 2004), and on steroid receptor targets (Fryer and Archer, 1998;DiRenzo et al, 2000;Belandia et al, 2002;Me´tivier et al, 2003;Link et al, 2005). Despite the growing knowledge of promoters regulated by hSWI/SNF, it is not well understood how the complex becomes localized and activated at various promoters; however, there is evidence for the involvement of signaling pathways.…”

“…The chromatin remodeling ability of hSWI/SNF has been shown to respond to various signaling pathways, including response to phosphoinositols (Zhao et al, 1998;Rando et al, 2002), the p38 pathway during skeletal myogenesis (Simone et al, 2004), interferons (Agalioti et al, 2000;Huang et al, 2002;Liu et al, 2002;Cui et al, 2004) and nuclear hormone receptors (Fryer and Archer, 1998;DiRenzo et al, 2000;Belandia et al, 2002;Me´tivier et al, 2003;Link et al, 2005). Phosphatidyl inositol 4,5-bisphosphate (PIP 2 ) has been shown to help increase the association of the SWI/SNF complex with the nuclear matrix (Zhao et al, 1998;Rando et al, 2002).…”

The functional role of the CARM1-SNF5 complex and its associated HMT activity in transcriptional activation by thyroid hormone receptor

“…Human SWI/SNF is heterogeneous and known to contain either Brm or its related protein Brg1, the ATPase subunits of the complexes (Wang et al, 1996). In transient transfection and in vitro transcription assays, both hBrm and hBrg1 can facilitate transcriptional activation by glucocorticoid receptor (GR), estrogen receptor (ER), and retinoic acid receptor (RAR) (Dilworth et al, 2000;DiRenzo et al, 2000). Accumulated evidence indicates that the coactivators CARM1 and ATP-dependent chromatin remodeling factor SWI/ SNF have critical functions in transcriptional activation by nuclear receptors.…”