title: Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells.
abstract: Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA polymerase II paused just downstream of transcriptional start sites. We explored Aire's collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire's caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115;
authors.forename: Kushagra
authors.initials: K
authors.lastname: Bansal
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065;
authors.forename: Uwe
authors.initials: U
authors.lastname: Schaefer
authors.affiliation: Epinova Discovery Performance Unit, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom;
authors.forename: Trevor
authors.initials: T
authors.lastname: Chapman
authors.affiliation: Epinova Discovery Performance Unit, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom;
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Rioja
authors.affiliation: Department of Microbiology and Immunology, University of California, San Francisco, CA 94143;
authors.forename: Irina
authors.initials: I
authors.lastname: Proekt
authors.affiliation: Diabetes Center, University of California, San Francisco, CA 94143;
authors.forename: Mark S
authors.initials: MS
authors.lastname: Anderson
authors.affiliation: Epinova Discovery Performance Unit, Immuno-Inflammation Therapy Area, Medicines Research Centre, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom;
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065;
authors.forename: Alexander
authors.initials: A
authors.lastname: Tarakhovsky
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Benoist
authors.affiliation: Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115 cbdm@hms.harvard.edu.
authors.forename: Diane
authors.initials: D
authors.lastname: Mathis
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology*; D061805:Transcription Elongation, Genetic / Q000187:drug effects; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D000096927:AIRE Protein; D000092468:Bromodomain Containing Proteins
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D008239:Lysine; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D014157:Transcription Factors; D000096927:AIRE Protein; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C568713:GSK1210151A
keywords: Aire; bromodomain protein; immunological tolerance; thymus; transcriptional elongation