JBC:BRD4通过调节表观遗传学来控制应激诱导的基因表达

可诱导的基因表达在许多细胞过程中起到了至关重要的作用，而转录延伸被认为是这种基因表达的关键限速步骤。蛋白BRD4(bromodomain-containing protein)能通过招募P-TEFb，对转录延伸进行调控，但它必须先从染色质上释放出来才能有效发挥作用。迄今为止，人们对BRD4的这种功能转变还并不了解。

为此，厦门大学和清华长三角研究院的研究人员展开了深入研究。他们发现，乙酰化的核小体组蛋白H4(H4K5ac/K8ac)是BRD4的结合位点，而磷酸化的组蛋白H3(H3S10ph)控制着BRD4的功能转变。

在正常情况下，H3S10磷酸化将BRD4锁定在染色质上。当细胞面临压力时，PP1α介导H3S10ph去磷酸化。此时，核小体的H4K5ac/K8ac就可以被HDAC1/2/3去乙酰化，释放染色质上结合的BRD4。BRD4释放出来之后，会招募P-TEFb促进条件诱导基因的表达。

研究总结道，压力条件会诱使染色质释放出BRD4，而这一过程依赖于组蛋白H3S10ph和H4K5ac/K8ac之间的相互作用，这种互作将PP1α和HDAC两条通路关联起来，对BRD4的功能转变进行调控。

结合研究团队之前对P-TEFb活化的了解，这篇文章为人们展示了一个严格调控转录延伸的复杂信号网络。

原文摘要：

Histone Cross-talk Connects Protein Phosphatase 1α (PP1α) andHistone Deacetylase (HDAC) Pathways to Regulate theFunctional Transition of Bromodomain-containing 4 (BRD4) forInducible Gene Expression

Xiangming Hu, Xiaodong Lu, Runzhong Liu, Nanping Ai, Zhenhua Cao,Yannan Li, Jiangfang Liu, Bin Yu, Kai Liu, Huiping Wang, Chao Zhou, Yu Wang,Aidong Han, Feng Ding and Ruichuan Chen

Transcription elongation has been recognized as a rate-limiting step for the expression of signal-inducible genes. Through recruitment of positive transcription elongation factor P-TEFb, the bromodomain-containing protein BRD4 plays critical roles in regulating the transcription elongation of a vast array of inducible genes that are important for multiple cellular processes. The diverse biological roles of BRD4 have been proposed to rely on its functional transition between chromatin targeting and transcription regulation. The signaling pathwaysand the molecular mechanism for regulating this transitionprocess, however, are largely unknown. Here, we report a novel role of phosphorylated Ser10 of histone H3 (H3S10ph) in governing the functional transition of BRD4. We identified thatthe acetylated lysines 5 and 8 of nucleosomal histone H4(H4K5ac/K8ac) is the BRD4 binding site, and the proteinphosphatase PP1α and class I histone deacetylase(HDAC1/2/3) signaling pathways are essential for the stress-induced BRD4 release from chromatin. In the unstressed state, phosphorylated H3S10 prevents the deacetylation ofnucleosomal H4K5ac/K8ac by HDAC1/2/3, thereby locking upthe majority of BRD4 onto chromatin. Upon stress, PP1α-mediated dephosphorylation of H3S10ph allows thedeacetylation of nucleosomal H4K5ac/K8ac by HDAC1/2/3,thereby leading to the release of chromatin-bound BRD4 forsubsequent recruitment of P-TEFb to enhance the expressionof inducible genes. Therefore, our study revealed a novel mechanism that the histone cross-talk between H3S10ph andH4K5ac/K8ac connects PP1α and HDACs to govern thefunctional transition of BRD4. Combined with previous studies on the regulation of P-TEFb activation, the intricate signaling network for the tight control of transcription elongation is established.

作者：生物帮