Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation.
Signal-induced Brd4 release from chromatin is essential for its role transition from chromatin targeting to transcriptional regulation.
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信号诱导的 Brd4 从染色质释放对于其从染色质靶向到转录调节的作用转变至关重要
DOI：
10.1093/nar/gkr698
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发表时间：
2011-12
影响因子：
14.9
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Ai N;Hu X;Ding F;Yu B;Wang H;Lu X;Zhang K;Li Y;Han A;Lin W;Liu R;Chen R
含溴结构域蛋白 Brd4 在有丝分裂过程中与染色体持续结合，在细胞分裂过程中传递表观遗传记忆。在间期期间，Brd4 还通过将正转录延伸因子 b (P-TEFb) 募集至启动子，在调节信号诱导基因的转录中发挥关键作用。然而，染色质结合的 Brd4 如何响应刺激而转变为转录调节模式，目前尚不清楚。在这里，通过分析紫外线或六亚甲基双乙酰胺处理过程中 Brd4 的动态，我们表明信号诱导的染色质结合 Brd4 的释放对于其功能转变至关重要。在未经处理的细胞中，几乎所有 Brd4 都与间期染色质相关。治疗后，Brd4 从染色质中释放，主要是由于信号触发的核小体组蛋白 H4 在乙酰化赖氨酸 5/8 (H4K5ac/K8ac) 处的去乙酰化。通过选择性地与因治疗而从无活性多亚基复合物中释放的 P-TEFb 转录活性形式结合，释放的 Brd4 介导将这种活性 P-TEFb 募集至启动子，从而增强延伸阶段的转录。因此，通过信号诱导的染色质释放以及与 P-TEFb 活性形式的选择性结合，染色质结合的 Brd4 转变其角色以介导 P-TEFb 的募集，从而调节信号诱导基因的转录延伸。
Bromodomain-containing protein Brd4 is shown to persistently associate with chromosomes during mitosis for transmitting epigenetic memory across cell divisions. During interphase, Brd4 also plays a key role in regulating the transcription of signal-inducible genes by recruiting positive transcription elongation factor b (P-TEFb) to promoters. How the chromatin-bound Brd4 transits into a transcriptional regulation mode in response to stimulation, however, is largely unknown. Here, by analyzing the dynamics of Brd4 during ultraviolet or hexamethylene bisacetamide treatment, we show that the signal-induced release of chromatin-bound Brd4 is essential for its functional transition. In untreated cells, almost all Brd4 is observed in association with interphase chromatin. Upon treatment, Brd4 is released from chromatin, mostly due to signal-triggered deacetylation of nucleosomal histone H4 at acetylated-lysine 5/8 (H4K5ac/K8ac). Through selective association with the transcriptional active form of P-TEFb that has been liberated from the inactive multi-subunit complex in response to treatment, the released Brd4 mediates the recruitment of this active P-TEFb to promoter, which enhances transcription at the stage of elongation. Thus, through signal-induced release from chromatin and selective association with the active form of P-TEFb, the chromatin-bound Brd4 switches its role to mediate the recruitment of P-TEFb for regulating the transcriptional elongation of signal-inducible genes.
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