Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells
Upregulated sirtuin 1 by miRNA-34a is required for smooth muscle cell differentiation from pluripotent stem cells
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miRNA-34a 上调 Sirtuin 1 是平滑肌细胞从多能干细胞分化所需的
DOI：
10.1038/cdd.2014.206
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发表时间：
2015-07-01
影响因子：
12.4
通讯作者：
Xiao, Q.
中科院分区：
文献类型：
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作者：
Yu, X.;Zhang, L.;Xiao, Q.
microRNA-34 a（miR-34 a）和sirtuin 1（SirT 1）在肿瘤生物学和长寿/衰老中已被广泛研究，但对其在多能干细胞向平滑肌细胞（SMC）分化中的功能作用知之甚少。使用完善的SMC分化模型，我们已经证明了miR-34 a在小鼠和人胚胎干细胞的SMC分化中具有重要作用。令人惊讶的是，去乙酰化酶sirtuin 1（SirT 1），预测的最高目标之一，在SMC分化过程中受到miR-34 a的正调控。从机制上讲，我们证明了miR-34 a促进分化干细胞停滞在G 0/G1期，并观察到在SMC分化后，miR-34 a和SirT 1 RNA掺入Ago 2-RISC复合物的显著减少。重要的是，我们已经确定了SirT 1作为一个转录激活剂在SMC基因程序的调节。最后，我们的数据表明，SirT 1调制周围的SMC基因启动子区域的H3 K9三甲基化的富集。综上所述，我们的数据揭示了一个特定的调控途径，miR-34 a正调控其靶基因SirT 1在细胞的上下文依赖性和序列特异性的方式，并建议在SMC分化的干细胞在体外和体内这一途径的功能作用。
microRNA-34a (miR-34a) and sirtuin 1 (SirT1) have been extensively studied in tumour biology and longevity/aging, but little is known about their functional roles in smooth muscle cell (SMC) differentiation from pluripotent stem cells. Using well-established SMC differentiation models, we have demonstrated that miR-34a has an important role in SMC differentiation from murine and human embryonic stem cells. Surprisingly, deacetylase sirtuin 1 (SirT1), one of the top predicted targets, was positively regulated by miR-34a during SMC differentiation. Mechanistically, we demonstrated that miR-34a promoted differentiating stem cells’ arrest at G0/G1 phase and observed a significantly decreased incorporation of miR-34a and SirT1 RNA into Ago2–RISC complex upon SMC differentiation. Importantly, we have identified SirT1 as a transcriptional activator in the regulation of SMC gene programme. Finally, our data showed that SirT1 modulated the enrichment of H3K9 tri-methylation around the SMC gene-promoter regions. Taken together, our data reveal a specific regulatory pathway that miR-34a positively regulates its target gene SirT1 in a cellular context-dependent and sequence-specific manner and suggest a functional role for this pathway in SMC differentiation from stem cells in vitro and in vivo.