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Bromodomain-containing Protein 4 regulates innate inflammation via modulation of alternative splicing

Morgan W Mann1, Yao Fu1, Robert L Gearhart2

  • 1Department of Medicine, University of Wisconsin - Madison, Madison, WI, United States.

Frontiers in Immunology
|July 12, 2023
PubMed
Abstract

Insights

Bromodomain-containing Protein 4 (BRD4) regulates mRNA processing, including alternative splicing of immune response genes, by controlling splicing factor expression during viral infections. This reveals a novel post-transcriptional role for BRD4 in innate immunity.

Area of Science:

  • Molecular Biology
  • Immunology
  • Gene Regulation

Background:

  • Bromodomain-containing Protein 4 (BRD4) is a key transcriptional regulator involved in cancer, inflammation, and fibrosis.
  • BRD4 inhibitors (BRD4i) are known to block pro-inflammatory cytokine release during viral infections.
  • The post-transcriptional regulatory roles of BRD4 remain largely unexplored despite its interaction with the spliceosome.

Purpose of the Study:

  • To investigate the hypothesis that BRD4 functions as a regulator of mRNA processing.
  • To elucidate BRD4's role in post-transcriptional gene regulation during viral infections.

Main Methods:

  • Utilized data-independent acquisition-parallel reaction monitoring (diaPASEF) coupled with RNA-sequencing.
  • Analyzed proteomic and transcriptomic landscapes of human small airway epithelial cells.
  • Cells were subjected to viral challenge and treated with BRD4 inhibitors.

Main Results:

  • BRD4 was found to regulate alternative splicing of critical genes such as Interferon-related Developmental Regulator 1 (IFRD1) and X-Box Binding Protein 1 (XBP1).
  • BRD4 is required for the expression of serine-arginine splicing factors and spliceosome components.
  • BRD4 influences the expression of Inositol-Requiring Enzyme 1 (IREα), impacting innate immune response and unfolded protein response (UPR).

Conclusions:

  • BRD4 plays a significant role in post-transcriptional RNA processing, specifically in modulating alternative splicing.
  • BRD4 controls the expression of splicing factors, thereby impacting innate immune signaling pathways during viral infections.
  • These findings expand the known functions of BRD4 beyond transcriptional elongation to include post-transcriptional regulation of mRNA processing.
Keywords:
BRD4IFRD1RSV (respiratory syncytial virus)alternative splicinginnate inflammatory responseunfolded protein response

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