Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome

TY - JOUR

T1 - Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome

AU - Weinert, Brian T.

AU - Narita, Takeo

AU - Satpathy, Shankha

AU - Srinivasan, Balaji

AU - Hansen, Bogi K

AU - Schölz, Christian

AU - Hamilton, William B.

AU - Zucconi, Beth E

AU - Wang, Wesley W

AU - Liu, Wenshe R

AU - Brickman, Joshua M

AU - Kesicki, Edward A

AU - Lai, Albert

AU - Bromberg, Kenneth D

AU - Cole, Philip A

AU - Choudhary, Chunaram

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018

Y1 - 2018

N2 - The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.

AB - The acetyltransferases CBP and p300 are multifunctional transcriptional co-activators. Here, we combined quantitative proteomics with CBP/p300-specific catalytic inhibitors, bromodomain inhibitor, and gene knockout to reveal a comprehensive map of regulated acetylation sites and their dynamic turnover rates. CBP/p300 acetylates thousands of sites, including signature histone sites and a multitude of sites on signaling effectors and enhancer-associated transcriptional regulators. Time-resolved acetylome analyses identified a subset of CBP/p300-regulated sites with very rapid (<30 min) acetylation turnover, revealing a dynamic balance between acetylation and deacetylation. Quantification of acetylation, mRNA, and protein abundance after CBP/p300 inhibition reveals a kinetically competent network of gene expression that strictly depends on CBP/p300-catalyzed rapid acetylation. Collectively, our in-depth acetylome analyses reveal systems attributes of CBP/p300 targets, and the resource dataset provides a framework for investigating CBP/p300 functions and for understanding the impact of small-molecule inhibitors targeting its catalytic and bromodomain activities.

KW - A-485

KW - acetylation

KW - acetylation kinetics

KW - bromodomain

KW - CBP

KW - enhancer

KW - gene transcription

KW - mass spectrometry

KW - p300

KW - proteomics

U2 - 10.1016/j.cell.2018.04.033

DO - 10.1016/j.cell.2018.04.033

M3 - Journal article

C2 - 29804834

SN - 0092-8674

VL - 174

SP - 231-244.e12

JO - Cell

JF - Cell

IS - 1

ER -