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

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. Metzger, Howard Y. Chang, Jesse M. Engreitz, Michael P. Snyder and Marlene Rabinovitch ()
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Jan-Renier Moonen: 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
Dan Li: Stanford University School of Medicine
Maxwell R. Mumbach: Stanford University School of Medicine
Fan Zhang: 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
Lingli Wang: Stanford University School of Medicine
Ross J. Metzger: Stanford University School of Medicine
Howard Y. Chang: Stanford University School of Medicine
Jesse M. Engreitz: Stanford University School of Medicine
Michael P. Snyder: Stanford University School of Medicine
Marlene Rabinovitch: Stanford University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32566-9

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