The bromodomain and extra-terminal domain (BET) family proteins, consisting of Brd2, Brd3, Brd4 and testis-specific Brdt, are widely recognized as major transcriptional regulators in biology, owing to their two characteristic tandem bromodomains (BrDs) binding to activated, lysine-acetylated histones and transcription factors to recruit transcription factors/effectors to target gene sites, and activate RNA polymerase II machinery for transcriptional elongation. Pharmacological inhibition of the BET proteins with pan-BET BrD inhibitors such as JQ1 has been shown to block broadly gene transcription in biology, and human cancer and inflammation disease models. Despite their prominent importance, however, our current knowledge of functional distinctions of the BET proteins has remained elusive, thus seriously hampering their potential as viable epigenetic drug targets for new disease treatment. As such, we propose to determine functional mechanisms of the BET proteins in gene transcriptional regulation in T-helper 17 (Th17) cell differentiation that has bee implicated in inflammatory disorders. Our study is built upon our recent discovery that Brd2 and Brd4 have distinct genomic deposition in Th17 cells, and exert different functions even at genes whose transcription they co-regulate. Importantly, we found that selective inhibition of the first bromodomain of BET proteins using our newly developed BrD inhibitor hinders primarily Th17 cell differentiation with beneficially minimal effects on Th1, Th2 and Treg cells, and also prevents adaptive T-cell transfer-induced colitis in mice. These favorable findings motivate us to determine the detailed molecular mechanisms of Brd2 and Brd4 functions in Th17 cell development, and establish a new therapeutic strategy for inflammatory disorders. Specifically, we aim to achieve three specific aims: (1) determine distinct mechanistic roles of the BET proteins in gene transcription of Th17 cells; (2) develop novel chemical modulators for BET BrDs; and (3) characterize genomic functions of BET proteins in Th17 cell differentiation. We envision our study not only to yield new mechanistic insights into Brd2 and Brd4 functions in transcriptional regulation of Th17 cell development in adaptive immunity, but also provide a clearer direction for developing more effective therapeutic treatment for inflammatory disorders.
Lineage-specific cell differentiation is controlled by gene transcription in chromatin that is fundamental to human biology and disease. While key transcriptional and chromatin regulators have been identified, it remains elusive as to how they work in concert to direct ordered gene expression in chromatin in response to physiological and environmental cues. In this study, we will investigate the fundamental transcriptional mechanisms required for specification of disease-causing cell types, and establish a new therapeutic strategy for future development of more effective and safer treatment of inflammatory disorders.
|Zaware, Nilesh; Zhou, Ming-Ming (2017) Chemical modulators for epigenome reader domains as emerging epigenetic therapies for cancer and inflammation. Curr Opin Chem Biol 39:116-125|
|Cheung, Kalung; Lu, Geming; Sharma, Rajal et al. (2017) BET N-terminal bromodomain inhibition selectively blocks Th17 cell differentiation and ameliorates colitis in mice. Proc Natl Acad Sci U S A 114:2952-2957|
|Cheung, Ka Lung; Zhang, Fan; Jaganathan, Anbalagan et al. (2017) Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation. Mol Cell 65:1068-1080.e5|
|Zhang, Qiang; Zeng, Lei; Zhao, Chengcheng et al. (2016) Structural Insights into Histone Crotonyl-Lysine Recognition by the AF9 YEATS Domain. Structure 24:1606-12|
|Aguilo, Francesca; Li, SiDe; Balasubramaniyan, Natarajan et al. (2016) Deposition of 5-Methylcytosine on Enhancer RNAs Enables the Coactivator Function of PGC-1?. Cell Rep 14:479-492|
|Meslamani, Jamel; Smith, Steven G; Sanchez, Roberto et al. (2016) Structural features and inhibitors of bromodomains. Drug Discov Today Technol 19:3-15|
|Zhang, Qiang; Zeng, Lei; Shen, Chen et al. (2016) Structural Mechanism of Transcriptional Regulator NSD3 Recognition by the ET Domain of BRD4. Structure 24:1201-8|