Chromatin remodelling by the glucocorticoid receptor requires the BRG1 complex

Abstract

The assembly of transcriptional regulatory DNA sequences into chromatin plays a fundamental role in modulating gene expression. The promoter of the mouse mammary-tumour virus (MMTV) is packaged into a regular array of nucleosomes when it becomes stably integrated into mammalian chromosomes, and has been used to investigate the relationship between chromatin architecture and transcriptional activation by the hormone-bound glucocorticoid and progesterone receptors. In mammalian cells that express both of these receptors, the progesterone receptor activates transcription from transiently transfected MMTV DNA but not from organized chromatin templates. Moreover, the activated progesterone receptor inhibits the chromatin remodelling and consequent transcriptional stimulation that is mediated by the glucocorticoid receptor. Here we investigate the mechanism of this inhibition by characterizing the interaction of the glucocorticoid receptor with transcriptional co-activator and chromatin remodelling protein complexes. We show that when this receptor is prevented from interacting with the hBRG1/BAF chromatin remodelling complex, it can activate transcription from transiently transfected DNA but not from organized chromatin templates. Our results indicate that it may be possible to separate the transcriptional activation and chromatin remodelling activities of proteins that interact with hormone receptors.

The SWI/SNF complex and cancer

“…The oncogenic transcription heterodimer activated protein-1 (AP-1) is known to be SWI/SNF dependent ; similarly, EKLF, which regulates b-hemogloblin synthesis, also requires this complex for its function (Armstrong et al, 1998;Lee et al, 1999). All known steroid receptors are functionally linked to SWI/SNF (Yoshinaga et al, 1992;Sumi-Ichinose et al, 1997;Fryer and Archer, 1998;Belandia et al, 2002;Inoue et al, 2002;Marshall et al, 2003;Flajollet et al, 2007). SWI/SNF has been linked to CD44, CEACAM1, E-cadherin and various integrins (Liu et al, 2001;Hendricks et al, 2004;Hill et al, 2004).…”

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).…”

Nuclear receptors and chromatin remodeling machinery

“…A role for ATP-dependent chromatin remodeling complexes in transcriptional regulation by steroid receptors was initially reported for GR in yeast studies (Muchardt and Yaniv, 1993;Yoshinaga et al, 1992;Fryer and Archer, 1998). To date, numerous reports suggest that ATP-dependent chromatin remodeling complexes influence ligand-induced transcriptional regulation through NRs (Acevedo and Kraus, 2004;Kinyamu and Archer, 2004).…”