Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
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DOI：
10.1093/nar/gkx159
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发表时间：
2017-05-05
影响因子：
14.9
通讯作者：
Minami T
中科院分区：
文献类型：
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作者：
Kanki Y;Nakaki R;Shimamura T;Matsunaga T;Yamamizu K;Katayama S;Suehiro JI;Osawa T;Aburatani H;Kodama T;Wada Y;Yamashita JK;Minami T
尽管小鼠胚胎干细胞(ES)向血管内皮细胞(ECs)分化的研究为研究血管发育的分子机制提供了一个很好的模型，但基因表达和染色质修饰的时间动力学还没有得到很好的研究。在这里，我们使用基于全基因组水平的H3K4me3和H3K27me3修饰的转录和表观基因组分析，分析了ES细胞的EC分化步骤和ECs特有的关键的表观遗传修饰。我们确定Gata2、FlI1、Sox7和Sox18是血管母细胞承诺先导因子ETV2表达后诱导的EC的主要调节因子。这些主调控基因在整个中胚层发育过程中都受到H3K27me3的抑制，但在血管内皮生长因子处理后迅速转变为组蛋白修饰。SiRNA敲除实验表明，这些调控因子不仅对于EC的正确分化是不可或缺的，而且对于阻止对其他紧密结合的谱系的承诺也是不可或缺的。总而言之，我们详细的表观遗传学分析可能为理解染色质信号的时间调控以及在EC承诺期间产生的基因表达谱提供一个先进的模型。这些研究可能为未来再生医学刺激血管内皮细胞的方法的发展提供参考。
Although studies of the differentiation from mouse embryonic stem (ES) cells to vascular endothelial cells (ECs) provide an excellent model for investigating the molecular mechanisms underlying vascular development, temporal dynamics of gene expression and chromatin modifications have not been well studied. Herein, using transcriptomic and epigenomic analyses based on H3K4me3 and H3K27me3 modifications at a genome-wide scale, we analysed the EC differentiation steps from ES cells and crucial epigenetic modifications unique to ECs. We determined that Gata2, Fli1, Sox7 and Sox18 are master regulators of EC that are induced following expression of the haemangioblast commitment pioneer factor, Etv2. These master regulator gene loci were repressed by H3K27me3 throughout the mesoderm period but rapidly transitioned to histone modification switching from H3K27me3 to H3K4me3 after treatment with vascular endothelial growth factor. SiRNA knockdown experiments indicated that these regulators are indispensable not only for proper EC differentiation but also for blocking the commitment to other closely aligned lineages. Collectively, our detailed epigenetic analysis may provide an advanced model for understanding temporal regulation of chromatin signatures and resulting gene expression profiles during EC commitment. These studies may inform the future development of methods to stimulate the vascular endothelium for regenerative medicine.