Genome-wide impact of the BRG1 SWI/SNF chromatin remodeler on the transforming growth factor beta transcriptional program.
The transcription factors Smad2 and Smad3 mediate a large set of gene responses induced by the cytokine transforming growth factor beta (TGFbeta), 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 TGFbeta 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 TGFbeta transcriptional program genome-wide. Most TGFbeta gene responses in human epithelial cells are dependent on BRG1 function. Remarkably, BRG1 is not required for the TGFbeta-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 TGFbeta action and suggest a widespread yet differential involvement of BRG1 SWI/SNF remodeler in the transcriptional response of many genes to this cytokine.
Xi
Qiaoran
Q
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
He
Wei
W
Zhang
Xiang H-F
XH
Le
Hong-Van
HV
Massagué
Joan
J
D002460:Cell Line; D002843:Chromatin / Q000648:ultrastructure*; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D015894:Genome, Human; D006801:Humans; D015603:Keratinocytes / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016366:Open Reading Frames; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D002843:Chromatin; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C084108:SMARCA4 protein, human; D004265:DNA Helicases