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. 2021 May 20;81(10):2166-2182.e6.
doi: 10.1016/j.molcel.2021.03.008. Epub 2021 Mar 24.

Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release

Takeo Narita  1 , Shinsuke Ito  2 , Yoshiki Higashijima  1 , Wai Kit Chu  1 , Katrin Neumann  3 , Jonas Walter  1 , Shankha Satpathy  1 , Tim Liebner  1 , William B Hamilton  4 , Elina Maskey  1 , Gabriela Prus  1 , Marika Shibata  2 , Vytautas Iesmantavicius  1 , Joshua M Brickman  4 , Konstantinos Anastassiadis  3 , Haruhiko Koseki  5 , Chunaram Choudhary  6
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Free article

Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release

Takeo Narita et al. Mol Cell. .
Free article

Abstract

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.

Keywords: BRD4; PIC assembly; TFIID; acetylation; bromodomain; deacetylases; enhancer; p300/CBP; pause release; super-enhancer.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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