@article{e8c119bc04424466b8a4e2120807e0d7,
title = "Enhancers are activated by p300/CBP activity-dependent PIC assembly, RNAPII recruitment, and pause release",
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",
author = "Takeo Narita and Shinsuke Ito and Yoshiki Higashijima and Chu, {Wai Kit} and Katrin Neumann and Jonas Walter and Shankha Satpathy and Tim Liebner and Hamilton, {William B.} and Elina Maskey and Gabriela Prus and Marika Shibata and Vytautas Iesmantavicius and Brickman, {Joshua M.} and Konstantinos Anastassiadis and Haruhiko Koseki and Chunaram Choudhary",
note = "Funding Information: We thank the members of our laboratories for their helpful discussions. The Novo Nordisk Foundation Center for Protein Research is financially supported by the Novo Nordisk Foundation ( NNF14CC0001 ). The Novo Nordisk Foundation Center for Stem Cell Biology is supported by the Novo Nordisk Foundation ( NNF17CC0027852 ). This work was funded by the European Commission FP7 grant ( SyBoSS FP7-242129 , www.syboss.eu ). C.C. was supported by the Hallas M{\o}ller Investigator Award ( NNF14OC0008541 ) from the Novo Nordisk Foundation . J.M.B. was supported by a grant from the Danish National Research Foundation (DNRF116). Y.H. was supported by a Grant-in-Aid for JSPS Overseas Postdoctoral Fellows . H.K. was supported by the Japan Agency for Medical Research and Development (AMED-CREST) ( 13417643 ) and Grant-in-Aid for Scientific Research on Innovative Areas ( JP19H05745 ). We thank Dr. Jiri Lukas for critical reading of the manuscript and providing helpful feedback. We thank the CPR Mass Spectrometry Platform, the CPR Imaging Platform, the CPR Big Data Management Platform, and the CPR and DanStem Genomics Platform for their assistance. Funding Information: We thank the members of our laboratories for their helpful discussions. The Novo Nordisk Foundation Center for Protein Research is financially supported by the Novo Nordisk Foundation (NNF14CC0001). The Novo Nordisk Foundation Center for Stem Cell Biology is supported by the Novo Nordisk Foundation (NNF17CC0027852). This work was funded by the European Commission FP7 grant (SyBoSS FP7-242129, www.syboss.eu). C.C. was supported by the Hallas M{\o}ller Investigator Award (NNF14OC0008541) from the Novo Nordisk Foundation. J.M.B. was supported by a grant from the Danish National Research Foundation (DNRF116). Y.H. was supported by a Grant-in-Aid for JSPS Overseas Postdoctoral Fellows. H.K. was supported by the Japan Agency for Medical Research and Development (AMED-CREST) (13417643) and Grant-in-Aid for Scientific Research on Innovative Areas (JP19H05745). We thank Dr. Jiri Lukas for critical reading of the manuscript and providing helpful feedback. We thank the CPR Mass Spectrometry Platform, the CPR Imaging Platform, the CPR Big Data Management Platform, and the CPR and DanStem Genomics Platform for their assistance. T.N. and C.C. conceived the project. T.N. S.I. Y.H. W.K.C. K.N. J.W. S.S. T.L. V.I. E.M. G.P. M.S. W.B.H. J.M.B. K.A. H.K. and C.C. designed and performed the research, analyzed the data, and interpreted the results. T.N. and C.C. wrote the manuscript with input from all of the other authors. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = may,
day = "20",
doi = "10.1016/j.molcel.2021.03.008",
language = "English",
volume = "81",
pages = "2166--2182.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "10",
}