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. We further 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.
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Kalung
authors.initials: K
authors.lastname: Cheung
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Geming
authors.initials: G
authors.lastname: Lu
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.
authors.forename: Adam
authors.initials: A
authors.lastname: Vincek
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Ruihua
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.|Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ju
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun 130061, China.
authors.forename: Xinye
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jamel
authors.initials: J
authors.lastname: Meslamani
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Feihong
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Hongfa
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Elena
authors.initials: E
authors.lastname: Rusinova
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Epigenetic Medicine, The First Hospital of 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.
authors.forename: Jiachi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Liang
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Michael
authors.initials: M
authors.lastname: Ohlmeyer
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.|Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Walsh
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
authors.forename: David Y
authors.initials: DY
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029; huabao.xiong@mssm.edu ming-ming.zhou@mssm.edu.|Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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; huabao.xiong@mssm.edu ming-ming.zhou@mssm.edu.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003092:Colitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
chemical_list: D008024:Ligands; D011506:Proteins; C000624329:bromodomain and extra-terminal domain protein, human; D000092468:Bromodomain Containing Proteins
keywords: Brd4; Th17 cell differentiation; bromodomain; chemical inhibitor; gene transcription