title: Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation.
abstract: 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 cyclin T1 and 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.
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Ka Lung
authors.initials: KL
authors.lastname: Cheung
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Anbalagan
authors.initials: A
authors.lastname: Jaganathan
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Rajal
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Konuma
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: June-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Geming
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Olson
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York, NY 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Huabao
authors.initials: H
authors.lastname: Xiong
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The First Hospital and Institute of Epigenetic Medicine, Jilin University, Changchun 130061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D000107:Acetylation; D056704:Adaptive Immunity; D000818:Animals; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000201:enzymology* / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056906:Cyclin T / Q000235:genetics / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D012319:RNA Polymerase II / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D058504:Th17 Cells / Q000201:enzymology* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000097722:Cohesins; D000099218:Interferon Regulatory Factor-4; D000092468:Bromodomain Containing Proteins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D056906:Cyclin T; D042863:Cyclin-Dependent Kinase 9; D050835:Interferon Regulatory Factors; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D000097722:Cohesins; D000099218:Interferon Regulatory Factor-4; C490844:Brd2 protein, mouse; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse; C503685:Ccnt1 protein, mouse; C000619698:Ctcf protein, mouse; C494087:Stat3 protein, mouse; C467972:Cdk9 protein, mouse
keywords: BRD2; BRD4; CTCF; Th17 cell differentiation; gene transcription; the cohesin complex