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Title: BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice

Abstract

T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4+T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. Furthermore, we show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowelmore » diseases.« less

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [3];  [1];  [3];  [3];  [1];  [1];  [1];  [1];  [1];  [1];  [2];  [1] more »;  [1];  [1];  [1];  [1];  [1];  [1];  [1] « less
  1. Icahn School of Medicine at Mount Sinai, New York, NY (United States)
  2. Icahn School of Medicine at Mount Sinai, New York, NY (United States); The First Hospital of Jilin Univ., Changchun (China)
  3. The First Hospital of Jilin Univ., Changchun (China)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); First Hospital of Jilin University; National Natural Science Foundation of China (NSFC); National Institutes of Health (NIH)
OSTI Identifier:
1409528
Report Number(s):
BNL-114580-2017-JA
Journal ID: ISSN 0027-8424
Grant/Contract Number:  
SC0012704; 81601409
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 114; Journal Issue: 11; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Th17 cell differentiation; gene transcription; Brd4; bromodomain; chemical inhibitor

Citation Formats

Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, and Zhou, Ming-Ming. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. United States: N. p., 2017. Web. doi:10.1073/pnas.1615601114.
Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, & Zhou, Ming-Ming. BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. United States. https://doi.org/10.1073/pnas.1615601114
Cheung, Kalung, Lu, Geming, Sharma, Rajal, Vincek, Adam, Zhang, Ruihua, Plotnikov, Alexander N., Zhang, Fan, Zhang, Qiang, Ju, Ying, Hu, Yuan, Zhao, Li, Han, Xinye, Meslamani, Jamel, Xu, Feihong, Jaganathan, Anbalagan, Shen, Tong, Zhu, Hongfa, Rusinova, Elena, Zeng, Lei, Zhou, Jiachi, Yang, Jianjun, Peng, Liang, Ohlmeyer, Michael, Walsh, Martin J., Zhang, David Y., Xiong, Huabao, and Zhou, Ming-Ming. 2017. "BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice". United States. https://doi.org/10.1073/pnas.1615601114. https://www.osti.gov/servlets/purl/1409528.
@article{osti_1409528,
title = {BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice},
author = {Cheung, Kalung and Lu, Geming and Sharma, Rajal and Vincek, Adam and Zhang, Ruihua and Plotnikov, Alexander N. and Zhang, Fan and Zhang, Qiang and Ju, Ying and Hu, Yuan and Zhao, Li and Han, Xinye and Meslamani, Jamel and Xu, Feihong and Jaganathan, Anbalagan and Shen, Tong and Zhu, Hongfa and Rusinova, Elena and Zeng, Lei and Zhou, Jiachi and Yang, Jianjun and Peng, Liang and Ohlmeyer, Michael and Walsh, Martin J. and Zhang, David Y. and Xiong, Huabao and Zhou, Ming-Ming},
abstractNote = {T-helper 17 (Th17) cells have important functions in adaptor immunity and have also been implicated in inflammatory disorders. The bromodomain and extraterminal domain (BET) family proteins regulate gene transcription during lineage-specific differentiation of naïve CD4+T cells to produce mature T-helper cells. Inhibition of acetyl-lysine binding of the BET proteins by pan-BET bromodomain (BrD) inhibitors, such as JQ1, broadly affects differentiation of Th17, Th1, and Th2 cells that have distinct immune functions, thus limiting their therapeutic potential. Whether these BET proteins represent viable new epigenetic drug targets for inflammatory disorders has remained an unanswered question. In this study, we report that selective inhibition of the first bromodomain of BET proteins with our newly designed small molecule MS402 inhibits primarily Th17 cell differentiation with a little or almost no effect on Th1 or Th2 and Treg cells. MS402 preferentially renders Brd4 binding to Th17 signature gene loci over those of housekeeping genes and reduces Brd4 recruitment of p-TEFb to phosphorylate and activate RNA polymerase II for transcription elongation. Furthermore, we show that MS402 prevents and ameliorates T-cell transfer-induced colitis in mice by blocking Th17 cell overdevelopment. Thus, selective pharmacological modulation of individual bromodomains likely represents a strategy for treatment of inflammatory bowel diseases.},
doi = {10.1073/pnas.1615601114},
url = {https://www.osti.gov/biblio/1409528}, journal = {Proceedings of the National Academy of Sciences of the United States of America},
issn = {0027-8424},
number = 11,
volume = 114,
place = {United States},
year = {Mon Mar 06 00:00:00 EST 2017},
month = {Mon Mar 06 00:00:00 EST 2017}
}

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Works referencing / citing this record:

Optimization of a “bump-and-hole” approach to allele-selective BET bromodomain inhibition
journal, January 2018


BET proteins in abnormal metabolism, inflammation, and the breast cancer microenvironment
journal, March 2018


Bromodomain biology and drug discovery
journal, October 2019


Molecular structures guide the engineering of chromatin
journal, June 2017


Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology
journal, December 2018


Computational study on the selective inhibition mechanism of MS402 to the first and second bromodomains of BRD4
journal, November 2018


Bromodomain and Extraterminal Proteins as Novel Epigenetic Targets for Renal Diseases
journal, November 2019


In silico design and molecular basis for the selectivity of Olinone toward the first over the second bromodomain of BRD4
journal, October 2019


Epigenetic Modification Mechanisms Involved in Inflammation and Fibrosis in Renal Pathology
journal, December 2018


Bromodomains: a new target class for drug development
journal, July 2019


Immunotherapy With Human Gamma Delta T Cells—Synergistic Potential of Epigenetic Drugs?
journal, March 2018