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

作者：Morgan Mann, Yao Fu, Robert Gearhart, Xiaofang Xu, David S. Roberts, Yi Li, Jia Zhou, Ying Ge, Allan R. Brasier · 发表于：Frontiers in Immunology · 年份：2023 · DOI：10.3389/fimmu.2023.1212770 · 被引用次数：13 · 研究领域：Protein Degradation and Inhibitors、Chromatin Remodeling and Cancer、RNA Research and Splicing

Introduction: Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In the context of airway viral infection, BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream epithelial plasticity. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not well understood. Given BRD4's interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing. Methods: To address this question, we combine data-independent analysis - parallel accumulation-serial fragmentation (diaPASEF) with RNA-sequencing to achieve deep and integrated coverage of the proteomic and transcriptomic landscapes of human small airway epithelial cells exposed to viral challenge and treated with BRD4i. Results: We discover that BRD4 regulates alternative splicing of key genes, including Interferon-related Developmental Regulator 1 (IFRD1) and X-Box Binding Protein 1 (XBP1), related to the innate immune response and the unfolded protein response (UPR). We identify requirement of BRD4 for expression of serine-arginine splicing factors, splicosome components and the Inositol-Requiring Enzyme 1 IREα affecting immediate early innate response and the UPR. Discussion: These findi...