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Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow

  1. Patrick A Murphy
  2. Vincent L Butty
  3. Paul L Boutz
  4. Shahinoor Begum
  5. Amy L Kimble
  6. Phillip A Sharp
  7. Christopher B Burge
  8. Richard O Hynes  Is a corresponding author
  1. UConn Health, United States
  2. Massachusetts Institute of Technology, United States
Research Article
  • Cited 2
  • Views 1,391
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Cite this article as: eLife 2018;7:e29494 doi: 10.7554/eLife.29494

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.

Article and author information

Author details

  1. Patrick A Murphy

    Center for Vascular Biology, UConn Health, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2956-1042
  2. Vincent L Butty

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Paul L Boutz

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Shahinoor Begum

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Amy L Kimble

    Center for Vascular Biology, UConn Health, Farmington, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Phillip A Sharp

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Christopher B Burge

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9047-5648
  8. Richard O Hynes

    Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    rohynes@mit.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7603-8396

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.

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.

Reviewing Editor

  1. Douglas L Black, University of California, Los Angeles, United States

Publication history

  1. Received: June 12, 2017
  2. Accepted: December 30, 2017
  3. Accepted Manuscript published: January 2, 2018 (version 1)
  4. 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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