Abstract
Endothelial cells (ECs) are constantly exposed to hemodynamic forces, which play a crucial role in regulating EC functions. Pulsatile laminar shear stress (PS), representing atheroprotective flow, maintains the anti-inflammation and homeostatic phenotype of ECs, but the comprehensive mechanism underlying the PS-repression of inflammatory genes remains to be determined. In this study, we investigated the role of chromatin organization in mediating the effects of PS on inflammatory gene expression in ECs. We demonstrated that PS induced the expression of histone methyltransferase SUV39H1 to promote heterochromatin formation via H3K9 trimethylation (H3K9me3) enrichment, a hallmark gene repression mechanism. SUV39H1 interacts with lamin-associated proteins and facilitates the perinuclear localization of the H3K9me3-enrichment. Silencing the lamin-associated protein emerin (EMD) not only led to the reductions of cytoskeletal F-actin formation and perinuclear H3K9me3 enrichment; but also the impairment of PS-induced SUV39H1 expression, H3K9me3 enrichment at E-selectin and vascular cell adhesion molecule 1 loci to revert their PS-repressed expression. Hence, EMD acts as a hub to transmit mechanical cues from the cytoskeleton to the nucleus and recruits SUV39H1, which regulate nuclear organization, chromatin state, and gene expression. These results accentuate the critical role of nuclear architecture in mechanotransduction and EC responses to mechanical stimuli.