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; Marlene Rabinovitch

doi:10.1038/s41467-022-32566-9

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

Nat Commun. 2022 Aug 23;13(1):4941. doi: 10.1038/s41467-022-32566-9.

Authors

Jan-Renier Moonen^#^{1

2

3

4}, James Chappell^#⁵, Minyi Shi⁵, Tsutomu Shinohara^{1

2

3

4}, Dan Li^{1

2

3}, Maxwell R Mumbach^{5

6}, Fan Zhang^{1

3}, Ramesh V Nair⁷, Joseph Nasser⁸, Daniel H Mai³, Shalina Taylor^{1

2

3}, Lingli Wang^{1

2

3

4}, Ross J Metzger^{1

3}, Howard Y Chang^{5

6}, Jesse M Engreitz^{4

5

8}, Michael P Snyder^{2

5

7}, Marlene Rabinovitch^{9

10

11

12}

Affiliations

¹ Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA.
³ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁴ BASE Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁵ Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁶ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁷ Stanford Center for Genomics and Personalized Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
⁸ Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
⁹ Vera Moulton Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, CA, 94305, USA. marlener@stanford.edu.
¹⁰ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, 94305, USA. marlener@stanford.edu.
¹¹ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, 94305, USA. marlener@stanford.edu.
¹² BASE Initiative, Betty Irene Moore Children's Heart Center, Lucile Packard Children's Hospital, Stanford University School of Medicine, Stanford, CA, 94305, USA. marlener@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Chromatin Assembly and Disassembly / genetics
Chromatin* / genetics
Endothelial Cells*
Nucleosomes / genetics
Regulatory Sequences, Nucleic Acid

Substances

Chromatin
Nucleosomes

Abstract

Publication types

MeSH terms

Substances

Grants and funding