TY - JOUR
T1 - Bromodomain-containing Protein 4 regulates innate inflammation via modulation of alternative splicing
AU - Mann, Morgan W.
AU - Fu, Yao
AU - Gearhart, Robert L.
AU - Xu, Xiaofang
AU - Roberts, David S.
AU - Li, Yi
AU - Zhou, Jia
AU - Ge, Ying
AU - Brasier, Allan
N1 - Funding Information:
This work was partially supported by NIH grants AI062885 (AB) and NCATS UL1TR002373 (AB). DSR would like to acknowledge support from the American Heart Association Predoctoral Fellowship Grant No. 832615/David S. Roberts/2021. JZ is also partly supported by the John D. Stobo, M.D. Distinguished Chair Endowment Fund. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. Acknowledgments
Funding Information:
The authors acknowledge the UW-Madison Human Proteomics Program Mass Spectrometry Facility (initially funded by the Wisconsin partnership funds) for support in obtaining mass spectrometry data and NIH S10OD018475 for the acquisition of ultra-high resolution mass spectrometer for biomedical research. We also thank Bruker for providing the timsTOF Pro mass spectrometer that was used in the study for the collection of all mass spectrometry data.
Publisher Copyright:
Copyright © 2023 Mann, Fu, Gearhart, Xu, Roberts, Li, Zhou, Ge and Brasier.
PY - 2023
Y1 - 2023
N2 - 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 findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing via modulating splicing factor expression in virus-induced innate signaling.
AB - 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 findings extend the transcriptional elongation-facilitating actions of BRD4 in control of post-transcriptional RNA processing via modulating splicing factor expression in virus-induced innate signaling.
KW - alternative splicing
KW - BRD4
KW - IFRD1
KW - innate inflammatory response
KW - RSV (respiratory syncytial virus)
KW - unfolded protein response
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U2 - 10.3389/fimmu.2023.1212770
DO - 10.3389/fimmu.2023.1212770
M3 - Article
C2 - 37435059
AN - SCOPUS:85164434877
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1212770
ER -