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

Author:
Weinert, Brian T., Narita, Takeo, Satpathy, Shankha, Srinivasan, Balaji, Hansen, Bogi K., Schölz, Christian, Hamilton, William B., Zucconi, Beth E., Wang, Wesley W., Liu, Wenshe R., Brickman, Joshua M., Kesicki, Edward A., Lai, Albert, Bromberg, Kenneth D., Cole, Philip A., Choudhary, Chunaram
Source:
Cell 2018 v.174 no.1 pp. 231-244.e12
ISSN:
0092-8674
Subject:
acetylation, acetyltransferases, data collection, gene targeting, histones, messenger RNA, proteomics, transcription (genetics), transcription factors
Abstract:
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.
Agid:
6052616