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KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress

Author

Listed:
  • Jan-Renier Moonen

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • James Chappell

    (Stanford University School of Medicine)

  • Minyi Shi

    (Stanford University School of Medicine)

  • Tsutomu Shinohara

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Dan Li

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Maxwell R. Mumbach

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Fan Zhang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ramesh V. Nair

    (Stanford University School of Medicine)

  • Joseph Nasser

    (Broad Institute of MIT and Harvard)

  • Daniel H. Mai

    (Stanford University School of Medicine)

  • Shalina Taylor

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Lingli Wang

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Ross J. Metzger

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Howard Y. Chang

    (Stanford University School of Medicine
    Stanford University School of Medicine)

  • Jesse M. Engreitz

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Broad Institute of MIT and Harvard)

  • Michael P. Snyder

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

  • Marlene Rabinovitch

    (Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine
    Stanford University School of Medicine)

Abstract

Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote this beneficial response. We show that under LSS, KLF4 interacts with the SWI/SNF nucleosome remodeling complex to increase accessibility at enhancer sites that promote the expression of homeostatic endothelial genes. By combining molecular and computational approaches we discover enhancers that loop to promoters of KLF4- and LSS-responsive genes that stabilize endothelial cells and suppress inflammation, such as BMPR2, SMAD5, and DUSP5. By linking enhancers to genes that they regulate under physiologic LSS, our work establishes a foundation for interpreting how non-coding DNA variants in these regions might disrupt protective gene expression to influence vascular disease.

Suggested Citation

  • Jan-Renier Moonen & James Chappell & Minyi Shi & Tsutomu Shinohara & Dan Li & Maxwell R. Mumbach & Fan Zhang & Ramesh V. Nair & Joseph Nasser & Daniel H. Mai & Shalina Taylor & Lingli Wang & Ross J. M, 2022. "KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32566-9
    DOI: 10.1038/s41467-022-32566-9
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