Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis.
Flow-Dependent Epigenetic DNA Methylation in Endothelial Gene Expression and Atherosclerosis.
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DOI：
10.1161/atvbaha.115.305042
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Jo H
中科院分区：
文献类型：
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作者：
Dunn J;Thabet S;Jo H
调控内皮细胞(EC)基因表达的表观遗传机制现已出现。DNA甲基化是最稳定的表观遗传标记，它赋予基因表达持续变化的能力。DNA甲基化不仅通过调节细胞类型特异性基因在整个分化过程中的表达而在呈现细胞特性方面发挥重要作用，而且越来越明显的是，DNA甲基化在维持EC内环境平衡和血管疾病发展中也发挥着关键作用。血流紊乱(d-flow)导致动脉粥样硬化，而稳定血流(S-flow)通过差异调节内皮细胞的基因表达来保护动脉粥样硬化。最近，我们和其他人发现，血流依赖的基因表达和动脉粥样硬化的发展受到依赖于DNA甲基转移酶(DNMT1和3A)的机制的调控。D-Flow在体外和体内均上调DNMT的表达，从而导致全基因组DNA甲基化改变和依赖于DNMT的全球基因表达改变。这些研究揭示了几个机械敏感基因，如HoxA5、Klf3和Klf4，它们的启动子被d-flow高甲基化，但被DNMT抑制剂如5-aza-2-脱氧胞苷拯救。这些发现为Flow控制表观DNA甲基化模式，进而改变内皮基因表达，调节血管生物学，并诱导动脉粥样硬化的机制提供了新的见解。
Epigenetic mechanisms that regulate endothelial cell (EC) gene expression are now emerging. DNA methylation is the most stable epigenetic mark that confers persisting changes in gene expression. Not only is DNA methylation important in rendering cell identity by regulating cell type-specific gene expression throughout differentiation, but it is becoming clear that DNA methylation also plays a key role in maintaining EC homeostasis and in vascular disease development. Disturbed blood flow (d-flow) causes atherosclerosis while stable flow (s-flow) protects against it by differentially regulating gene expression in ECs. Recently, we and others have shown that flow-dependent gene expression and atherosclerosis development are regulated by mechanisms dependent on DNA methyltransferases (DNMT1 and 3A). D-flow upregulates DNMT expression both in vitro and in vivo which leads to genome-wide DNA methylation alterations and global gene expression changes in a DNMT-dependent manner. These studies revealed several mechanosensitive genes, such as HoxA5, Klf3, and Klf4, whose promoters were hypermethylated by d-flow, but rescued by DNMT inhibitors such as 5Aza-2-deoxycytidine. These findings provide new insight into the mechanism by which flow controls epigenomic DNA methylation patterns, which in turn alters endothelial gene expression, regulates vascular biology, and induces atherosclerosis.