BRD7, a novel PBAF-specific SWI/SNF subunit, is required for target gene activation and repression in embryonic stem cells.
The composition of chromatin-remodeling complexes dictates how these enzymes control transcriptional programs and cellular identity. In the present study we investigated the composition of SWI/SNF complexes in embryonic stem cells (ESCs). In contrast to differentiated cells, ESCs have a biased incorporation of certain paralogous SWI/SNF subunits with low levels of BRM, BAF170, and ARID1B. Upon differentiation, the expression of these subunits increases, resulting in a higher diversity of compositionally distinct SWI/SNF enzymes. We also identified BRD7 as a novel component of the Polybromo-associated BRG1-associated factor (PBAF) complex in both ESCs and differentiated cells. Using short hairpin RNA-mediated depletion of BRG1, we showed that SWI/SNF can function as both a repressor and an activator in pluripotent cells, regulating expression of developmental modifiers and signaling components such as Nodal, ADAMTS1, BMI-1, CRABP1, and thyroid releasing hormone. Knockdown studies of PBAF-specific BRD7 and of a signature subunit within the BAF complex, ARID1A, showed that these two subcomplexes affect SWI/SNF target genes differentially, in some cases even antagonistically. This may be due to their different biochemical properties. Finally we examined the role of SWI/SNF in regulating its target genes during differentiation. We found that SWI/SNF affects recruitment of components of the preinitiation complex in a promoter-specific manner to modulate transcription positively or negatively. Taken together, our results provide insight into the function of compositionally diverse SWI/SNF enzymes that underlie their inherent gene-specific mode of action.
Kaeser
Matthias D
MD
Regulatory Biology, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Aslanian
Aaron
A
Dong
Meng-Qiu
MQ
Yates
John R
JR
Emerson
Beverly M
BM
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism* / Q000502:physiology*; D004265:DNA Helicases / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry; D009687:Nuclear Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D002868:Chromosomal Proteins, Non-Histone; D004265:DNA Helicases; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; C485694:BRD7 protein, human; D000092468:Bromodomain Containing Proteins; C400206:Brd7 protein, mouse; C445179:SWI-SNF-B chromatin-remodeling complex; C084108:SMARCA4 protein, human; C513194:Smarca4 protein, mouse