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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 (2018): Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome. In: Cell, Vol. 174, No. 1: pp. 231-244
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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 turn-over 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.