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.
Cell Res. 2010 Dec;20(12):1345-60. doi: 10.1038/cr.2010.155. Epub 2010 Nov 16.
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.
SWI/SNF 染色质重塑复合物利用 ATP 水解产生的能量来重新定位核小体并调节人类基因的表达。在这里，我们研究了人类 BRM（hBrm）和 BRG1 相关基因 1（Brg1）作为 SWI/SNF 复合物的 ATP 酶亚基在调节人类基因中的作用。我们的结果表明，hBrm 和 Brg1 均可在体外与信号转导和转录激活因子 1（Stat1）相互作用。然而，天然形式的 Stat1 仅将 hBrm 招募到 IFNγ 激活序列（GAS）的单个基因上；相比之下，在应激诱导的磷酸化形式下，Stat1 主要与 Brg1 结合。在基础条件下，天然 Stat1 将 hBrm 招募到 GAS 上，并存在于 hsp90α 基因上的 mSin3/HDAC 共抑制复合物中，该基因表现出紧凑的染色质结构。在热激时，hBrm 被 p300 乙酰化并从共抑制复合物中解离出来，磷酸化 Stat1 增加，与 Brg1 结合并将其招募到 GAS，从而导致基因的诱导增加。这种 hBrm/Brg1 转换也发生在热激细胞中所有三个被检查的免疫基因的 GAS 上；然而，这种转换仅在 IFNγ 暴露于特定细胞类型时发生。无论刺激如何，GAS 上的 hBrm/Brg1 转换都会增加基因活性。我们的数据与 hBrm/Brg1 转换是基因对热激或 IFNγ 刺激的反应性的指示这一假说一致，并且可能代表体内基因表达的“开-关”开关。
