KLF4 recruits SWI/SNF to increase chromatin accessibility and reprogram the endothelial enhancer landscape under laminar shear stress.
Jan Renier MoonenJames ChappellMinyi ShiTsutomu ShinoharaDan LiMaxwell R MumbachFan ZhangRamesh V NairJoseph NasserDaniel H MaiShalina TaylorLingli WangRoss J MetzgerHoward Y ChangJesse M EngreitzMichael Paul SnyderMarlene RabinovitchPublished in: Nature communications (2022)
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.
Keyphrases
- transcription factor
- genome wide identification
- endothelial cells
- genome wide
- gene expression
- dna methylation
- binding protein
- copy number
- bioinformatics analysis
- genome wide analysis
- high glucose
- oxidative stress
- poor prognosis
- single molecule
- pulmonary arterial hypertension
- single cell
- vascular endothelial growth factor
- circulating tumor
- pulmonary hypertension
- cell free
- signaling pathway