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

Brian T. Weinert; Takeo Narita; Shankha Satpathy; Balaji Srinivasan; Bogi K Hansen; Christian Schölz; William B. Hamilton; Beth E Zucconi; Wesley W Wang; Wenshe R Liu; Joshua M Brickman; Edward A Kesicki; Albert Lai; Kenneth D Bromberg; Philip A Cole; Chunaram Choudhary

doi:10.1016/j.cell.2018.04.033

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

Brian T. Weinert, Takeo Narita, Shankha Satpathy, Balaji Srinivasan, Bogi K Hansen, Christian Schölz, William B. Hamilton, Beth E Zucconi, Wesley W Wang, Wenshe R Liu, Joshua M Brickman, Edward A Kesicki, Albert Lai, Kenneth D Bromberg, Philip A Cole, Chunaram Choudhary

91 Citations (Scopus)

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.

Original language	English
Journal	Cell
Volume	174
Issue number	1
Pages (from-to)	231-244.e12
Number of pages	27
ISSN	0092-8674
DOIs	https://doi.org/10.1016/j.cell.2018.04.033
Publication status	Published - 2018

Keywords

A-485
acetylation
acetylation kinetics
bromodomain
CBP
enhancer
gene transcription
mass spectrometry
p300
proteomics

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10.1016/j.cell.2018.04.033

http://www.cell.com/article/S0092867418305269/pdf

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Weinert, B. T., Narita, T., Satpathy, S., Srinivasan, B., Hansen, B. K., Schölz, C., Hamilton, W. B., Zucconi, B. E., Wang, W. W., Liu, W. R., Brickman, J. M., Kesicki, E. A., Lai, A., Bromberg, K. D., Cole, P. A., & Choudhary, C. (2018). Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome. Cell, 174(1), 231-244.e12. https://doi.org/10.1016/j.cell.2018.04.033

Weinert, BT , Narita, T, Satpathy, S, Srinivasan, B, Hansen, BK, Schölz, C, Hamilton, WB, Zucconi, BE, Wang, WW, Liu, WR, Brickman, JM, Kesicki, EA, Lai, A, Bromberg, KD, Cole, PA & Choudhary, C 2018, 'Time-Resolved Analysis Reveals Rapid Dynamics and Broad Scope of the CBP/p300 Acetylome', Cell, vol. 174, no. 1, pp. 231-244.e12. https://doi.org/10.1016/j.cell.2018.04.033

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

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.",

keywords = "A-485, acetylation, acetylation kinetics, bromodomain, CBP, enhancer, gene transcription, mass spectrometry, p300, proteomics",

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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

PY - 2018

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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 -

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

Abstract

Keywords

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