Zobrazit v EDS

H3K27Me3 abundance is associated with a decreased barrier function of endothelial cells by directly silencing VE-cadherin expression

Uloženo v:
Podrobná bibliografie
Název: H3K27Me3 abundance is associated with a decreased barrier function of endothelial cells by directly silencing VE-cadherin expression
Autoři: Jolien Fledderus, Byambasuren Vanchin, Linda Brouwer, Timara Kuiper, Rianne M. Jongman, M. van Meurs, Martin C. Harmsen, Guido Krenning
Zdroj: Atherosclerosis. 406:119242
Informace o vydavateli: Elsevier BV, 2025.
Rok vydání: 2025
Témata: Cultured, Mechanotransduction, Cadherins/genetics, Cells, Histones/metabolism, Stress, Mechanical, Capillary Permeability, Atherosclerosis/genetics, CD/genetics, Genetic, Humans, Gene Silencing, Cellular, Enhancer of Zeste Homolog 2 Protein/genetics, Antigens, Human Umbilical Vein Endothelial Cells/metabolism, Epigenesis
Popis: Atherosclerosis develops mainly in predisposed, atheroprone regions characterised by the presence of disturbed flow i.e. oscillatory shear stress (OSS). OSS can induce endothelial cell (EC) activation, disruption of the EC barrier and increased permeability. The mechanisms that underly the loss of the EC barrier integrity are still incompletely understood. Enhancer of zeste homolog 2 (EZH2) and its epigenetic silencing mark H3K27Me3 are increased in the endothelium at atheroprone areas where EC barrier disruption is most prominent. Therefore, we hypothesized that increased H3K27Me3 abundance at atheroprone areas affects the barrier function of the endothelium.A knockdown model of EZH2 in human umbilical vein EC (HUVEC) was used for RNA-seq, to identify differentially expressed genes involved in EC barrier function. Additionally, the effect of OSS on endothelial gene expression was studied by applying laminar shear stress (LSS) on y-shaped slides as a model to mimic atheroprotective and atheroprone areas in vivo. Results were corroborated by a functional study of the barrier function using trans-endothelial electric resistance (TEER).An increased H3K27Me3 abundance is present in areas under OSS, this coincides with a decreased expression of VE-cadherin. Differentially expression (DE) analysis of EZH2KD HUVEC vs control, revealed that EZH2 regulates genes involved in cell-cell adhesion and leukocyte transmigration. Chromatin immunoprecipitation (ChIP) of H3K27Me3 showed that H3K27Me3 directly silenced CDH5 gene expression. Additionally, a reduction of EZH2 appears to increase EC barrier stability.Decreased H3K27Me3 abundance in ECs is beneficial for the formation and integrity of the EC barrier.
Druh dokumentu: Article
Jazyk: English
ISSN: 0021-9150
DOI: 10.1016/j.atherosclerosis.2025.119242
Přístupová URL adresa: https://pubmed.ncbi.nlm.nih.gov/40398293
https://hdl.handle.net/11370/32d9fd09-67d6-4a98-81b2-6eac74380763
https://research.rug.nl/en/publications/32d9fd09-67d6-4a98-81b2-6eac74380763
https://doi.org/10.1016/j.atherosclerosis.2025.119242
Rights: CC BY
Přístupové číslo: edsair.doi.dedup.....42499c12387fdc6fda3e431ff00d664a
Databáze: OpenAIRE
Popis
Abstrakt:Atherosclerosis develops mainly in predisposed, atheroprone regions characterised by the presence of disturbed flow i.e. oscillatory shear stress (OSS). OSS can induce endothelial cell (EC) activation, disruption of the EC barrier and increased permeability. The mechanisms that underly the loss of the EC barrier integrity are still incompletely understood. Enhancer of zeste homolog 2 (EZH2) and its epigenetic silencing mark H3K27Me3 are increased in the endothelium at atheroprone areas where EC barrier disruption is most prominent. Therefore, we hypothesized that increased H3K27Me3 abundance at atheroprone areas affects the barrier function of the endothelium.A knockdown model of EZH2 in human umbilical vein EC (HUVEC) was used for RNA-seq, to identify differentially expressed genes involved in EC barrier function. Additionally, the effect of OSS on endothelial gene expression was studied by applying laminar shear stress (LSS) on y-shaped slides as a model to mimic atheroprotective and atheroprone areas in vivo. Results were corroborated by a functional study of the barrier function using trans-endothelial electric resistance (TEER).An increased H3K27Me3 abundance is present in areas under OSS, this coincides with a decreased expression of VE-cadherin. Differentially expression (DE) analysis of EZH2KD HUVEC vs control, revealed that EZH2 regulates genes involved in cell-cell adhesion and leukocyte transmigration. Chromatin immunoprecipitation (ChIP) of H3K27Me3 showed that H3K27Me3 directly silenced CDH5 gene expression. Additionally, a reduction of EZH2 appears to increase EC barrier stability.Decreased H3K27Me3 abundance in ECs is beneficial for the formation and integrity of the EC barrier.
ISSN:00219150
DOI:10.1016/j.atherosclerosis.2025.119242