101. Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells
- Author
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Yoshida, Hideyuki, Bansal, Kushagra, Schaefer, Uwe, Chapman, Trevor, Rioja, Inmaculada, Proekt, Irina, Anderson, Mark S, Prinjha, Rab K, Tarakhovsky, Alexander, Benoist, Christophe, and Mathis, Diane
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Genetics ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Acetylation ,Amino Acid Sequence ,Animals ,Epithelial Cells ,Gene Expression Regulation ,HEK293 Cells ,Heterocyclic Compounds ,4 or More Rings ,Humans ,Immune Tolerance ,Lysine ,Mice ,Models ,Biological ,Molecular Sequence Data ,Mutation ,Nuclear Proteins ,Phosphorylation ,Positive Transcriptional Elongation Factor B ,Protein Binding ,Protein Interaction Mapping ,Protein Structure ,Tertiary ,RNA Splicing ,Stromal Cells ,Thymus Gland ,Transcription Elongation ,Genetic ,Transcription Factors ,Transcriptome ,immunological tolerance ,thymus ,Aire ,bromodomain protein ,transcriptional elongation - 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.
- Published
- 2015