Genome-wide Impact of the BRG1 SWI/SNF Chromatin Remodeler on the Transforming Growth Factor β Transcriptional Program

The transcription factors Smad2 and Smad3 mediate a large set of gene responses induced by the cytokine transforming growth factor β (TGFβ), but the extent to which their function depends on chromatin remodeling remains to be defined. We observed interactions between these two Smads and BRG1, BAF250b, BAF170, and BAF155, which are core components of the SWI/SNF chromatin-remodeling complex. Smad2 and Smad3 have similar affinity for these components in vitro, and their interactions are primarily mediated by BRG1. In vivo, however, BRG1 predominantly interacts with Smad3, and this interaction is enhanced by TGFβ stimulation. Our results suggest that BRG1 is incorporated into transcriptional complexes that are formed by activated Smads in the nucleus, on target promoters. Using BRG1-deficient cell systems, we defined the BRG1 dependence of the TGFβ transcriptional program genome-wide. Most TGFβ gene responses in human epithelial cells are dependent on BRG1 function. Remarkably, BRG1 is not required for the TGFβ-mediated induction of SMAD7 and SNON, which encode key mediators of negative feedback in this pathway. Our results provide a genome-wide scope of the participation of BRG1 in TGFβ action and suggest a widespread yet differential involvement of BRG1 SWI/SNF remodeler in the transcriptional response of many genes to this cytokine. The transcription factors Smad2 and Smad3 mediate a large set of gene responses induced by the cytokine transforming growth factor β (TGFβ), but the extent to which their function depends on chromatin remodeling remains to be defined. We observed interactions between these two Smads and BRG1, BAF250b, BAF170, and BAF155, which are core components of the SWI/SNF chromatin-remodeling complex. Smad2 and Smad3 have similar affinity for these components in vitro, and their interactions are primarily mediated by BRG1. In vivo, however, BRG1 predominantly interacts with Smad3, and this interaction is enhanced by TGFβ stimulation. Our results suggest that BRG1 is incorporated into transcriptional complexes that are formed by activated Smads in the nucleus, on target promoters. Using BRG1-deficient cell systems, we defined the BRG1 dependence of the TGFβ transcriptional program genome-wide. Most TGFβ gene responses in human epithelial cells are dependent on BRG1 function. Remarkably, BRG1 is not required for the TGFβ-mediated induction of SMAD7 and SNON, which encode key mediators of negative feedback in this pathway. Our results provide a genome-wide scope of the participation of BRG1 in TGFβ action and suggest a widespread yet differential involvement of BRG1 SWI/SNF remodeler in the transcriptional response of many genes to this cytokine. Genomic DNA is packed into chromatin units or nucleosomes whose accessibility determines the ability of particular genes to respond to regulatory inputs (1Kornberg R.D. Thomas J.O. Science. 1974; 184: 865-868Crossref PubMed Scopus (583) Google Scholar, 2Kayne P.S. Kim U.J. Han M. Mullen J.R. Yoshizaki F. Grunstein M. Cell. 1988; 55: 27-39Abstract Full Text PDF PubMed Scopus (312) Google Scholar, 3Han M. Grunstein M. Cell. 1988; 55: 1137-1145Abstract Full Text PDF PubMed Scopus (313) Google Scholar). Various classes of ATP-dependent chromatin remodeling factors (remodelers) have been identified that control the accessibility of DNA. Remodelers act on histone-DNA contacts to induce nucleosome sliding, DNA looping, or complete dissociation of histones from DNA (4Flaus A. Owen-Hughes T. Curr. Opin. Genet. Dev. 2004; 14: 165-173Crossref PubMed Scopus (134) Google Scholar, 5Mohrmann L. Verrijzer C.P. 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EMBO J. 2006; 25: 4490-4502Crossref PubMed Scopus (111) Google Scholar). that Smad to DNA not histone to the chromatin but SWI/SNF complexes to provide chromatin remodeling The identification of protein interactions between Smad2 and SWI/SNF an opportunity to investigate the role of this chromatin remodeling complex in the response to a cytokine. The is on this a genome-wide to the for BRG1 in TGFβ gene responses in human epithelial The results provide a of the dependence of the TGFβ transcriptional program on BRG1 SWI/SNF function. and in with cells in with cells in with and and from include and and and affinity from has been M. J. Massague J. Dev. 1999; PubMed Scopus Google Scholar). by of M.L. Sif S. Narlikar G.J. Kingston R.E. Mol. Cell. 1999; 3: 247-253Abstract Full Text Full Text PDF PubMed Scopus (507) Google Scholar) with and the into a Y. Massague J. S. A. PubMed Scopus Google Scholar). by of with and and the into of the of from by with the with and into the of BRG1 and by L. 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Full Text Full Text PDF PubMed Scopus Google which is SWI/SNF components (4Flaus A. Owen-Hughes T. Curr. Opin. Genet. Dev. 2004; 14: 165-173Crossref PubMed Scopus (134) Google Scholar, 6Narlikar G.J. Fan H.Y. Kingston R.E. Cell. 2002; 108: 475-487Abstract Full Text Full Text PDF PubMed Scopus (1242) Google Scholar, 8Saha A. Wittmeyer J. Cairns B.R. Nat. Rev. Mol. Cell. Biol. 2006; 7: 437-447Crossref PubMed Scopus (446) Google Scholar, 9Smith C.L. Peterson C.L. Curr. Top Dev. Biol. 2005; 65: 115-148Crossref PubMed Scopus (155) Google Scholar, C.W. Orkin S.H. Nat. Rev. Cancer. 2004; 4: 133-142Crossref PubMed Scopus (486) Google Scholar). results by from cells BRG1 and Smad the similar affinity of SWI/SNF for Smad2 and Smad3 in in BRG1 with Smad3 with Smad2 In to Smad3, the of Smad2 DNA Y. Wang L. H. Massague J. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). 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Biol. 2005; 25: PubMed Scopus Google and and and J. these a of BRG1 to genes that the interaction between BRG1 and is by TGFβ to these results suggest that Smad transcriptional complexes the of BRG1 to these The of BRG1 little or on the of to these as by that transcriptional complexes to these target BRG1 The of BRG1 to the and SMAD7 in the cells is in with the of these TGFβ responses to BRG1 The of BRG1 to the The that the response to TGFβ in these cells that this gene response is of BRG1. the of BRG1 to the not in BRG1 the response of to TGFβ these that the Smad complex BRG1 the Smad complexes or In with the extent of the TGFβ response in of these the of BRG1 the of in the of in the of and not in the of and these results classes of TGFβ target genes that are by the of the Smad complexes for BRG1 or the of their dependence on BRG1. of TGFβ in an to the dependence of the TGFβ transcriptional program on BRG1, we the TGFβ response in epithelial which are to growth by a of human cell this response S. 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