title: A switch from hBrm to Brg1 at IFNγ-activated sequences mediates the activation of human genes.
abstract: The SWI/SNF chromatin-remodeling complexes utilize energy from ATP hydrolysis to reposition nucleosomes and regulate the expression of human genes. Here, we studied the roles of human Brahma (hBrm) and Brahma-related gene 1 (Brg1), the ATPase subunits of the SWI/SNF complexes, in regulating human genes. Our results indicate that both hBrm and Brg1 interact with Signal transducer and activator of transcription (Stat) 1 in vitro. However, Stat1 in its native form only recruits hBrm to IFNγ-activated sequences (GAS) of individual genes; by contrast, in a stress-induced phosphorylated form, Stat1 mainly binds to Brg1. Under basal conditions, hBrm is recruited by native Stat1 to the GAS and exists in a mSin3/HDAC co-repressor complex on the hsp90α gene, which shows a compact chromatin structure. Upon heat-shock, hBrm is acetylated by p300 and dissociates from the co-repressor complex, which the phosphorylated Stat1 is increased, and binds and recruits Brg1 to the GAS, leading to elevated induction of the gene. This hBrm/Brg1 switch also occurs at the GAS of all of the three examined immune genes in heat-shocked cells; however, this switch only occurs in specific cell types upon exposure to IFNγ. Regardless of the stimulus, the hBrm/Brg1 switch at the GAS elicits an increase in gene activity. Our data are consistent with the hypothesis that the hBrm/Brg1 switch is an indicator of the responsiveness of a gene to heat-shock or IFNγ stimulation and may represent an "on-off switch" of gene expression in vivo.
authors.affiliation: National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 Dongdan Santiao, Beijing 100005, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Mo-Bin
authors.initials: MB
authors.lastname: Cheng
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhong
authors.forename: Hui
authors.initials: H
authors.lastname: Dai
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Ning-Hua
authors.initials: NH
authors.lastname: Wu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yu-Fei
authors.initials: YF
authors.lastname: Shen
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D042002:Chromatin Assembly and Disassembly; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D004265:DNA Helicases; D018841:HSP90 Heat-Shock Proteins; D007371:Interferon-gamma; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C084011:SMARCA2 protein, human; C084108:SMARCA4 protein, human