Bromodomain-containing Protein 4 Regulates Innate Inflammation in Airway Epithelial Cells via Modulation of Alternative Splicing.
Morgan W MannYao FuXiaofang XuDavid S RobertsYi LiJia ZhouYing GeAllan R BrasierPublished in: bioRxiv : the preprint server for biology (2023)
Bromodomain-containing Protein 4 (BRD4) is a transcriptional regulator which coordinates gene expression programs controlling cancer biology, inflammation, and fibrosis. In airway viral infection, non-toxic BRD4-specific inhibitors (BRD4i) block the release of pro-inflammatory cytokines and prevent downstream remodeling. Although the chromatin modifying functions of BRD4 in inducible gene expression have been extensively investigated, its roles in post-transcriptional regulation are not as well understood. Based on its interaction with the transcriptional elongation complex and spliceosome, we hypothesize that BRD4 is a functional regulator of mRNA processing. 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. The transcript-level data was further interrogated for alternative splicing analysis, and the resulting data sets were correlated to identify pathways subject to post-transcriptional regulation. 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, respectively. These findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing in innate signaling.
Keyphrases
- gene expression
- immune response
- transcription factor
- binding protein
- oxidative stress
- electronic health record
- big data
- single cell
- endothelial cells
- protein protein
- healthcare
- amino acid
- genome wide
- heat shock
- toll like receptor
- genome wide identification
- young adults
- mass spectrometry
- deep learning
- artificial intelligence
- papillary thyroid
- anti inflammatory
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