Pulsatile flow induces chromatin interaction with lamin-associated proteins to enrich H3K9 methylation in endothelial cells

• 成果类型: Article
• 署名作者: Chen, Li- Jing; Li, Julie Yi- Shuan; Nguyen, Phu; Norwich, Gerard; Wang, Yingxiao; Teng, Dayu; Shiu, Yan- Ting; Shyy, John Y. J.; Chien, Shu
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; University of Southern California; Utah System of Higher Education; University of Utah; US Department of Veterans Affairs; Veterans Health Administration (VHA); Utah System of Higher Education; University of Utah; Utah System of Higher Education; University of Utah; University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11053
• DOI: 10.1073/pnas.2424566122
• 发表日期: 2025-03-25
• 关键词: nuclear-envelope; shear-stress; mechanical regulation; gene-expression; reveals; genome; ORGANIZATION; maintenance; FORCE; hdac3

摘要

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.