BRD7, a Novel PBAF-specific SWI/SNF Subunit, Is Required for Target Gene Activation and Repression in Embryonic Stem Cells
BRD7, a Novel PBAF-specific SWI/SNF Subunit, Is Required for Target Gene Activation and Repression in Embryonic Stem Cells
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DOI：
10.1074/jbc.m806061200
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发表时间：
2008-11-21
影响因子：
4.8
通讯作者：
Emerson, Beverly M.
中科院分区：
文献类型：
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作者：
Kaeser, Matthias D.;Aslanian, Aaron;Emerson, Beverly M.
染色质重塑复合物的组成决定了这些酶如何控制转录程序和细胞身份。在本研究中，我们调查了SWI/SNF复合物在胚胎干细胞（ESCs）的组成。与分化的细胞相反，ESC具有某些旁系同源SWI/SNF亚基的偏向性掺入，具有低水平的BRM、BAF 170和ARID 1B。分化后，这些亚基的表达增加，导致组成上不同的SWI/SNF酶的更高多样性。我们还确定BRD 7作为一种新的成分的多溴相关的BRG 1相关因子（PBAF）复合物在胚胎干细胞和分化的细胞。利用短发夹RNA介导的BRG 1缺失，我们发现SWI/SNF在多能细胞中既可以作为抑制剂又可以作为激活剂，调节发育修饰剂和信号传导成分如Nodal、ADAMTS 1、BMI-1、CRABP 1和甲状腺释放激素的表达。PBAF特异性BRD 7和BAF复合物ARID 1A内的特征亚基的敲低研究表明，这两个亚复合物差异地影响SWI/SNF靶基因，在某些情况下甚至是拮抗性的。这可能是由于它们不同的生物化学特性。最后，我们研究了SWI/SNF在分化过程中调节其靶基因的作用。我们发现，SWI/SNF影响招聘的组件的preinitiation复杂的启动子特异性的方式来调节转录积极或消极。总之，我们的研究结果提供了深入了解组成不同的SWI/SNF酶的功能，这些酶是其固有的基因特异性作用模式的基础。
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.