Browsing by Author "Zhou, Ming-Ming"

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    Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation
    (Cell Press, 2017-03-16) Cheung, Ka Lung; Zhang, Fan; Jaganathan, Anbalagan; Sharma, Rajal; Zhang, Qiang; Konuma, Tsuyoshi; Shen, Tong; Lee, June-Yong; Ren, Chunyan; Chen, Chih-Hung; Lu, Geming; Olson, Matthew R.; Zhang, Weijia; Kaplan, Mark H.; Littman, Dan R.; Walsh, Martin J.; Xiong, Huabao; Zeng, Lei; Zhou, Ming-Ming; Pediatrics, School of Medicine
    The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T-helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclinT1/Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity., , Cheung et al. uncover both separate and interdependent Brd2 and Brd4 genomic functions in potentiating the genetic program required for Th17 cell development and adaptive immunity. Brd2 interacts with transcription factor Stat3 and chromatin insulator CTCF/cohesin complex to support enhancer assembly, whereas Brd4 temporally controls RNA PolII for transcription elongation.
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    HIPK2 directs cell type-specific regulation of STAT3 transcriptional activity in Th17 cell differentiation
    (National Academy of Science, 2022) Cheung, Ka Lung; Jaganathan, Anbalagan; Hu, Yuan; Xu, Feihong; Lejeune, Alannah; Sharma, Rajal; Caescu, Cristina I.; Meslamani, Jamel; Vincek, Adam; Zhang, Fan; Lee, Kyung; Zaware, Nilesh; Qayum, Amina Abdul; Ren, Chunyan; Kaplan, Mark H.; He, John Cijiang; Xiong, Huabao; Zhou, Ming-Ming; Microbiology and Immunology, School of Medicine
    SignificanceSTAT3 (signal transducer and activator of transcription 3) is a master transcription factor that organizes cellular responses to cytokines and growth factors and is implicated in inflammatory disorders. STAT3 is a well-recognized therapeutic target for human cancer and inflammatory disorders, but how its function is regulated in a cell type-specific manner has been a major outstanding question. We discovered that Stat3 imposes self-directed regulation through controlling transcription of its own regulator homeodomain-interacting protein kinase 2 (Hipk2) in a T helper 17 (Th17) cell-specific manner. Our validation of the functional importance of the Stat3-Hipk2 axis in Th17 cell development in the pathogenesis of T cell-induced colitis in mice suggests an approach to therapeutically treat inflammatory bowel diseases that currently lack a safe and effective therapy.