Histone Cross-talk Connects Protein Phosphatase 1 α (PP1 α) and Histone Deacetylase (HDAC) Pathways to Regulate the Functional Transition of Bromodomain-containing 4 (BRD4) for Inducible Gene Expression
Histone Cross-talk Connects Protein Phosphatase 1 α (PP1 α) and Histone Deacetylase (HDAC) Pathways to Regulate the Functional Transition of Bromodomain-containing 4 (BRD4) for Inducible Gene Expression
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DOI：
10.1074/jbc.m114.570812
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发表时间：
2014-08-15
影响因子：
4.8
通讯作者：
Chen, Ruichuan
中科院分区：
文献类型：
--
作者：
Hu, Xiangming;Lu, Xiaodong;Chen, Ruichuan
转录延伸已被认为是信号诱导基因表达的限速步骤。通过募集正转录延伸因子P-TEFb，含溴结构域蛋白BRD 4在调节大量诱导型基因的转录延伸中起关键作用，所述诱导型基因对于多种细胞过程是重要的。BRD 4的多种生物学作用已被提出依赖于其在染色质靶向和转录调节之间的功能转变。然而，调节这种转变过程的信号通路和分子机制在很大程度上是未知的。在此，我们报道了组蛋白H3的磷酸化Ser（10）（H3 S10 ph）在调控BRD 4功能转变中的新作用。我们确定了核小体组蛋白H4的乙酰化赖氨酸5和8（H4 K5 ac/K8 ac）是BRD 4结合位点，蛋白磷酸酶PP 1 α和I类组蛋白脱乙酰酶（HDAC 1/2/3）信号通路对于应激诱导的BRD 4从染色质释放是必不可少的。在非应激状态下，磷酸化的H3 S10阻止核小体H4 K5 ac/K8 ac被HDAC 1/2/3脱乙酰化，从而将大部分BRD 4锁定在染色质上。在应激时，PP 1 α介导的H3 S10 ph的去磷酸化允许核小体H4 K5 ac/K8 ac被HDAC 1/2/3去乙酰化，从而导致染色质结合的BRD 4的释放，用于随后募集P-TEFb以增强诱导型基因的表达。因此，我们的研究揭示了一种新的机制，即H3 S10 ph和H4 K5 ac/K8 ac之间的组蛋白串扰将PP 1 alpha和HDAC连接起来，以控制BRD 4的功能转变。结合前人对P-TEFb激活调控的研究，建立了紧密控制转录延伸的复杂信号网络。
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 pathways and the molecular mechanism for regulating this transition process, however, are largely unknown. Here, we report a novel role of phosphorylated Ser(10) of histone H3 (H3S10ph) in governing the functional transition of BRD4. We identified that the acetylated lysines 5 and 8 of nucleosomal histone H4 (H4K5ac/K8ac) is the BRD4 binding site, and the protein phosphatase PP1 alpha 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 of nucleosomal H4K5ac/K8ac by HDAC1/2/3, thereby locking up the majority of BRD4 onto chromatin. Upon stress, PP1 alpha-mediated dephosphorylation of H3S10ph allows the deacetylation of nucleosomal H4K5ac/K8ac by HDAC1/2/3, thereby leading to the release of chromatin-bound BRD4 for subsequent recruitment of P-TEFb to enhance the expression of inducible genes. Therefore, our study revealed a novel mechanism that the histone cross-talk between H3S10ph and H4K5ac/K8ac connects PP1 alpha and HDACs to govern the functional 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.