Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

Ka Lung Cheung; Fan Zhang; Anbalagan Jaganathan; Rajal Sharma; Qiang Zhang; Tsuyoshi Konuma; Tong Shen; June-Yong Lee; Chunyan Ren; Chih-Hung Chen; Geming Lu; Matthew R Olson; Weijia Zhang; Mark H Kaplan; Dan R Littman; Martin J Walsh; Huabao Xiong; Lei Zeng; Ming-Ming Zhou

doi:10.1016/j.molcel.2016.12.022

Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation

Mol Cell. 2017 Mar 16;65(6):1068-1080.e5. doi: 10.1016/j.molcel.2016.12.022. Epub 2017 Mar 3.

Authors

Ka Lung Cheung¹, Fan Zhang², Anbalagan Jaganathan¹, Rajal Sharma¹, Qiang Zhang³, Tsuyoshi Konuma¹, Tong Shen¹, June-Yong Lee⁴, Chunyan Ren¹, Chih-Hung Chen⁵, Geming Lu⁶, Matthew R Olson⁷, Weijia Zhang⁸, Mark H Kaplan⁷, Dan R Littman⁹, Martin J Walsh¹⁰, Huabao Xiong⁶, Lei Zeng³, Ming-Ming Zhou¹¹

Affiliations

¹ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
² 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.
³ 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.
⁴ The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA.
⁵ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁶ 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.
⁷ Department of Pediatrics and Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁸ Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
⁹ 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.
¹⁰ 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.
¹¹ Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: ming-ming.zhou@mssm.edu.

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.

Keywords: BRD2; BRD4; CTCF; Th17 cell differentiation; gene transcription; the cohesin complex.

MeSH terms

Acetylation
Adaptive Immunity*
Animals
CCCTC-Binding Factor
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Differentiation*
Cells, Cultured
Chromatin / enzymology*
Chromatin / genetics
Chromosomal Proteins, Non-Histone / chemistry
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
Cohesins
Cyclin T / genetics
Cyclin T / metabolism
Cyclin-Dependent Kinase 9 / genetics
Cyclin-Dependent Kinase 9 / metabolism
Gene Expression Regulation
Interferon Regulatory Factors / genetics
Interferon Regulatory Factors / metabolism
Mice, Inbred C57BL
Models, Molecular
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Phenotype
Phosphorylation
Protein Binding
Protein Interaction Domains and Motifs
RNA Interference
RNA Polymerase II / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
STAT3 Transcription Factor / genetics
STAT3 Transcription Factor / metabolism
Signal Transduction
Structure-Activity Relationship
Th17 Cells / enzymology*
Th17 Cells / immunology
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic*
Transfection

Substances

Brd2 protein, mouse
Brd4 protein, mouse
CCCTC-Binding Factor
Ccnt1 protein, mouse
Cell Cycle Proteins
Chromatin
Chromosomal Proteins, Non-Histone
Ctcf protein, mouse
Cyclin T
Interferon Regulatory Factors
Nuclear Proteins
Repressor Proteins
STAT3 Transcription Factor
Stat3 protein, mouse
Transcription Factors
interferon regulatory factor-4
Cdk9 protein, mouse
Cyclin-Dependent Kinase 9
RNA Polymerase II

Abstract

MeSH terms

Substances

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