Brd4 bridges the transcriptional regulators, Aire and P-TEFb, to promote elongation of peripheral-tissue antigen transcripts in thymic stromal cells

Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):E4448-57. doi: 10.1073/pnas.1512081112. Epub 2015 Jul 27.

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.

Keywords: Aire; bromodomain protein; immunological tolerance; thymus; transcriptional elongation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIRE Protein
  • Acetylation / drug effects
  • Amino Acid Sequence
  • Animals
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Gene Expression Regulation* / drug effects
  • HEK293 Cells
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Immune Tolerance / drug effects
  • Immune Tolerance / genetics
  • Lysine / metabolism
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • Phosphorylation / drug effects
  • Positive Transcriptional Elongation Factor B / metabolism*
  • Protein Binding / drug effects
  • Protein Interaction Mapping
  • Protein Structure, Tertiary
  • RNA Splicing / drug effects
  • RNA Splicing / genetics
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism
  • Thymus Gland / cytology*
  • Transcription Elongation, Genetic* / drug effects
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome / genetics

Substances

  • Brd4 protein, mouse
  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • Nuclear Proteins
  • Transcription Factors
  • Positive Transcriptional Elongation Factor B
  • Lysine