Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release
Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release
复制标题
DOI：
10.1016/j.molcel.2021.03.008
复制
发表时间：
2021-05-20
期刊：
影响因子：
16
通讯作者：
Choudhary, Chunaram
中科院分区：
文献类型：
--
作者：
Narita, Takeo;Ito, Shinsuke;Choudhary, Chunaram
后生动物特异性乙酰转移酶p300/CBP参与激活信号诱导的、增强子介导的细胞类型特异性基因的转录。然而，p300/CBP活性依赖性转录激活的整体动力学和机制仍然知之甚少。我们进行了全基因组的时间分辨分析，表明增强子和超增强子通过p300/ cbp催化的乙酰化动态激活，通过相反的去乙酰化酶活性动态失活，并且动态乙酰化直接有助于在非常快（分钟）的时间尺度内维持细胞特性。乙酰转移酶活性对于p300/CBP和转录因子的募集是必不可少的，但对于促进TFIID和RNAPII在几乎所有增强子和增强子调控基因上的募集是必不可少的。这表明起始前复合物组装是转录周期中一个动态控制的步骤，并揭示了p300/ cbp催化的乙酰化是特异性促进增强子调控基因转录起始的信号。我们提出p300/CBP活性利用“招募-释放”机制同时促进RNAPII的招募和暂停释放，从而实现增强子介导的转录的动力学激活。
The metazoan-specific acetyltransferase p300/CBP is involved in activating signal-induced, enhancer-mediated transcription of cell-type-specific genes. However, the global kinetics and mechanisms of p300/CBP activity-dependent transcription activation remain poorly understood. We performed genome-wide, time-resolved analyses to show that enhancers and super-enhancers are dynamically activated through p300/ CBP-catalyzed acetylation, deactivated by the opposing deacetylase activity, and kinetic acetylation directly contributes to maintaining cell identity at very rapid (minutes) timescales. The acetyltransferase activity is dispensable for the recruitment of p300/CBP and transcription factors but essential for promoting the recruitment of TFIID and RNAPII at virtually all enhancers and enhancer-regulated genes. This identifies pre-initiation complex assembly as a dynamically controlled step in the transcription cycle and reveals p300/CBP-catalyzed acetylation as the signal that specifically promotes transcription initiation at enhancer-regulated genes. We propose that p300/CBP activity uses a "recruit-and-release" mechanism to simultaneously promote RNAPII recruitment and pause release and thereby enables kinetic activation of enhancer-mediated transcription.