Elucidation of the mechanism of nucleosomal structural change mediated by histone modifications

启动子区域周围的核小体在响应各种信号（如组蛋白的乙酰化和甲基化）时被分解转录。虽然已经报道了组蛋白乙酰化识别溴结构域与参与核小体拆卸的因子之间的相互作用，但尚未获得组蛋白修饰与核小体拆卸之间的结构基础。我们在3.3 A分辨率下测定了组蛋白伴侣细胞周期基因1 （CCG1）相互作用因子A/抗沉默功能1 （CIA/ASF1）与转录因子IID的CCG1/TAF1/TAF(II)250亚基中双bromodomain复合物的晶体结构。结构、生化和生物学研究表明，双溴结构域和CIA/ASF1之间的相互作用是它们共定位、组蛋白排出和活性启动子区域pol II进入所必需的。此外，目前的晶体结构具有将组蛋白乙酰化和CIA/ asf1介导的组蛋白逐出联系起来的特征。这些发现表明CIA/ASF1和双溴结构域之间的分子复合物在活性启动子区域的位点特异性组蛋白排出中起关键作用。我们在本研究中提出的模型是从组蛋白修饰到核小体结构变化的生物信号传导的初始结构模型（hi-MOST模型）。

Nucleosomes around the promoter region are disassembled for transcription in response to various signals, such as acetylation and methylation of histones. Although the interactions between histone-acetylation- recognizing bromodomains and factors involved in nucleosome disassembly have been reported, no structural basis connecting histone modifications and nucleosome disassembly has been obtained. We determined at 3.3 A resolution the crystal structure of histone chaperone cell cycle gene 1 (CCG1) interacting factor A/antisilencing function 1 (CIA/ASF1) in complex with the double bromodomain in the CCG1/TAF1/TAF(II)250 subunit of transcription factor IID. Structural, biochemical, and biological studies suggested that interaction between double bromodomain and CIA/ASF1 is required for their colocalization, histone eviction, and pol II entry at active promoter regions. Furthermore, the present crystal structure has characteristics that can connect histone acetylation and CIA/ASF1-mediated histone eviction. These findings suggest that the molecular complex between CIA/ASF1 and the double bromodomain plays a key role in site-specific histone eviction at active promoter regions. The model we propose in this study is the initial structure-based model of the biological signaling fromhistone modifications to structural change of the nucleosome (hi-MOST model).