Molecular basis of CD4 repression by the Swi/Snf-like BAF chromatin remodeling complex.
Molecular basis of CD4 repression by the Swi/Snf-like BAF chromatin remodeling complex.
复制标题
Swi/Snf 样 BAF 染色质重塑复合物抑制 CD4 的分子基础。
DOI：
10.1002/eji.200838909
复制
发表时间：
2009
影响因子：
5.4
通讯作者：
Chi,Tian
中科院分区：
文献类型：
--
作者：
Wan,Mimi;Zhang,Jianmin;Lai,Dazhi;Jani,Anant;Prestone-Hurlburt,Paula;Zhao,Lulu;Ramachandran,Aruna;Schnitzler,GavinR;Chi,Tian
Brg 1/Brm相关因子（BAF）染色质重塑复合物直接结合CD 4沉默子，并且在T细胞发育期间对CD 4抑制至关重要，因为ATP酶亚基Brg 1的缺失或BAF 57的显性负突变均会损害早期胸腺细胞中的CD 4抑制。特别地，BAF 57在体外重塑核小体或在体内使BAF复合物与CD 4沉默子结合。因此，目前尚不清楚BAF 57依赖性CD 4抑制是否涉及染色质重塑，如果是，重塑如何转化为CD 4抑制。在这里，我们表明，核小体在CD 4沉默占据多个翻译框架。BAF 57显性失活突变体不改变这些框架，但降低了整个沉默子的可及性，而不影响侧翼区域，伴随着连接体组蛋白H1的局部积累和Runx 1的驱逐，Runx 1是直接结合CD 4沉默子的CD 4转录的关键阻遏物。我们的数据表明，精确的核小体定位对于CD 4沉默子功能并不重要，BAF 57参与重塑CD 4沉默子上含H1的染色质，这使得Runx 1能够进入沉默子并抑制CD 4。除了BAF 57之外，BAF复合物中的多个其他亚基对于体外染色质重塑也是不可或缺的。我们的数据表明，这些亚基也可以帮助重塑染色质在一个步骤后，招聘的BAF复合物的靶基因。
The Brg1/Brm‐associated factor (BAF) chromatin remodeling complex directly binds the CD4 silencer and is essential for CD4 repression during T‐cell development, because deletion of the ATPase subunit Brg1 or a dominant negative mutant of BAF57 each impairs CD4 repression in early thymocytes. Paradoxically, BAF57 is dispensable for remodeling nucleosomesin vitroor for binding of the BAF complex to the CD4 silencerin vivo. Thus, it is unclear whether BAF57‐dependent CD4 repression involves chromatin remodeling and, if so, how the remodeling translates into CD4 repression. Here we show that nucleosomes at the CD4 silencer occupy multiple translational frames. BAF57 dominant negative mutant does not alter these frames, but reduces the accessibility of the entire silencer without affecting the flanking regions, concomitant with localized accumulation of linker histone H1 and eviction of Runx1, a key repressor of CD4 transcription that directly binds the CD4 silencer. Our data indicate that precise nucleosome positioning is not critical for the CD4 silencer function and that BAF57 participates in remodeling H1‐containing chromatin at the CD4 silencer, which enables Runx1 to access the silencer and repress CD4. In addition to BAF57, multiple other subunits in the BAF complex are also dispensable for chromatin remodellingin vitro. Our data suggest that these subunits could also help remodel chromatin at a step after the recruitment of the BAF complex to target genes.