Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow
- UConn Health, United States
- Massachusetts Institute of Technology, United States
Abstract
Low and disturbed blood flow drives the progression of arterial diseases including atherosclerosis and aneurysms. The endothelial response to flow and its interactions with recruited platelets and leukocytes determine disease progression. Here, we report widespread changes in alternative splicing of pre-mRNA in the flow-activated murine arterial endothelium in vivo. Alternative splicing was suppressed by depletion of platelets and macrophages recruited to the arterial endothelium under low and disturbed flow. Binding motifs for the Rbfox-family are enriched adjacent to many of the regulated exons. Endothelial deletion of Rbfox2, the only family member expressed in arterial endothelium, suppresses a subset of the changes in transcription and RNA splicing induced by low flow. Our data reveal an alternative splicing program activated by Rbfox2 in the endothelium on recruitment of platelets and macrophages and demonstrate its relevance in transcriptional responses during flow-driven vascular inflammation.
Data availability
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Alternative RNA Splicing in the Endothelium Mediated in Part by Rbfox2 Regulates the Arterial Response to Low FlowPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE101826), password protected until publication.
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Transcriptome-wide Regulation of Splicing and mRNA Localization by Muscleblind ProteinsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE39911).
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Rbfox2 controls autoregulation in RNA binding protein networksPublicly available at the NCBI Gene Expression Omnibus (accession no:GSE54794).
Article and author information
Author details
Christopher B Burge
Funding
National Heart, Lung, and Blood Institute (F32-HL110484)
- Patrick A Murphy
National Cancer Institute (P30-CA14051)
- Vincent L Butty
Howard Hughes Medical Institute (Investigator Award)
- Richard O Hynes
National Heart, Lung, and Blood Institute (K99/R00-HL125727)
- Patrick A Murphy
National Heart, Lung, and Blood Institute (PO1-HL66105)
- Patrick A Murphy
National Institute of General Medical Sciences (R01-GM034277)
- Phillip A Sharp
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Douglas L Black, University of California, Los Angeles, United States
Ethics
Animal experimentation: All mice were housed and handled in accordance with protocols approved by the Massachusetts Institute of Technology Committee on Animal Care (CAC) protocol (0415-033-18). All surgery was performed under isoflurane anesthesia with post-operative analgesia.
Version history
- Received: June 12, 2017
- Accepted: December 30, 2017
- Accepted Manuscript published: January 2, 2018 (version 1)
- Version of Record published: January 17, 2018 (version 2)
Copyright
© 2018, Murphy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow
eLife 7:e29494.
https://doi.org/10.7554/eLife.29494
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