The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence.
The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence.
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DOI：
10.1007/s10456-015-9485-2
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发表时间：
2016-01
期刊：
影响因子：
9.8
通讯作者：
Krenning G
中科院分区：
文献类型：
--
作者：
Maleszewska M;Vanchin B;Harmsen MC;Krenning G
高均匀流体切应力(FSS)具有动脉粥样硬化保护作用，并通过激活下游介质如MAPK7(ERK5)来保护内皮细胞的表型和功能。内皮细胞对FSS的反应归功于机械转导。然而，所产生的信号如何在表观遗传水平上被整合和分解仍然难以捉摸。我们推测多梳甲基转移酶EZH2参与了FSS对人内皮细胞的影响。我们发现FSS降低了多梳甲基转移酶EZH2的表达。尽管MAPK7同时被激活，但MAPK7途径并不直接影响EZH2的转录。有趣的是，EZH2的敲除激活了内皮细胞中保护性的MAPK7信号，即使在没有FSS的情况下也是如此。为了了解FSS下调EZH2的表达对血管内皮细胞转录组的影响，我们进行了RNA-seq和差异基因表达分析。我们确定了依赖于EZH2和FSS的候选基因组。其中，基因本体论过度表达分析显示与细胞周期相关的基因高度丰富，表明细胞增殖发生了变化。事实上，EZH2的缺失强烈地抑制了内皮细胞的增殖，表明细胞周期停滞。伴随而来的CCNA表达减少提示内皮细胞向静止表型转变。进一步的生物信息学分析表明，TXNIP可能是EZH2与细胞周期相关基因网络之间的中介。我们的数据表明，EZH2是一个FSS反应基因。降低的EZH2水平增强了动脉粥样硬化保护的MAPK7信号的激活。FSS下EZH2的减少介导了细胞周期相关基因网络表达的减少，从而使细胞进入静止状态。因此，EZH2在FSS的内皮保护作用中起重要作用。本文的在线版本(doi：10.1007/s10456-0159485-2)包含补充材料，授权用户可以使用。
High uniform fluid shear stress (FSS) is atheroprotective and preserves the endothelial phenotype and function through activation of downstream mediators such as MAPK7 (Erk5). Endothelial cells respond to FSS thanks to mechanotransduction. However, how the resulting signaling is integrated and resolved at the epigenetic level remains elusive. We hypothesized that Polycomb methyltransferase EZH2 is involved in the effects of FSS in human endothelial cells. We showed that FSS decreases the expression of the Polycomb methyltransferase EZH2. Despite simultaneous activation of MAPK7, MAPK7 pathway does not directly influence the transcription of EZH2. Interestingly though, the knockdown of EZH2 activates the protective MAPK7 signaling in endothelial cells, even in the absence of FSS. To understand the influence of the FSS-decreased expression of EZH2 on endothelial transcriptome, we performed RNA-seq and differential gene expression analysis. We identified candidate groups of genes dependent on both EZH2 and FSS. Among those, Gene Ontology overrepresentation analysis revealed highly significant enrichment of the cell cycle-related genes, suggesting changes in proliferation. Indeed, the depletion of EZH2 strongly inhibited endothelial proliferation, indicating cell cycle arrest. The concomitant decrease in CCNA expression suggests the transition of endothelial cells into a quiescent phenotype. Further bioinformatical analysis suggested TXNIP as a possible mediator between EZH2 and cell cycle-related gene network. Our data show that EZH2 is a FSS-responsive gene. Decreased EZH2 levels enhance the activation of the atheroprotective MAPK7 signaling. Decrease in EZH2 under FSS mediates the decrease in the expression of the network of cell cycle-related genes, which allows the cells to enter quiescence. EZH2 is therefore important for the protective effects of FSS in endothelium. The online version of this article (doi:10.1007/s10456-015-9485-2) contains supplementary material, which is available to authorized users.