miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues.
miRNAs regulate SIRT1 expression during mouse embryonic stem cell differentiation and in adult mouse tissues.
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DOI：
10.18632/aging.100176
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发表时间：
2010-07
期刊：
影响因子：
--
通讯作者：
Verdin E
中科院分区：
文献类型：
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作者：
Saunders LR;Sharma AD;Tawney J;Nakagawa M;Okita K;Yamanaka S;Willenbring H;Verdin E
SIRT1被认为是应激反应、复制衰老、炎症、代谢和衰老的重要调节因子。SIRT1的表达受转录和转录后调控，其酶活性受NAD+水平和相互作用蛋白的控制。我们发现，在小鼠胚胎干细胞(MESCs)中，SIRT1蛋白水平远远高于分化组织。在mESC分化过程中，miRNAs转录后下调SIRT1，并在分化组织中维持低水平的SIRT1表达。具体地说，miR-181a和b、miR-9、miR-204、miR-199B和miR-135a抑制SIRT1蛋白的表达。在mESC分化过程中最早诱导的针对SIRT1的miRNA mir-9的抑制阻止了SIRT1的下调。相反，在小鼠胚胎成纤维细胞(MEF)重新编程为诱导多能干细胞(IPS)的过程中，SIRT1蛋白水平在转录后上调。MiRNAs对SIRT1蛋白水平的调节可能为治疗组织特异性调节SIRT1表达和将体细胞重新编程为iPS细胞提供新的机会。
SIRT1 is increasingly recognized as a critical regulator of stress responses, replicative senescence, inflammation, metabolism, and aging. SIRT1 expression is regulated transcriptionally and post-transcriptionally, and its enzymatic activity is controlled by NAD+ levels and interacting proteins. We found that SIRT1 protein levels were much higher in mouse embryonic stem cells (mESCs) than in differentiated tissues. miRNAs post-transcriptionally downregulated SIRT1 during mESC differentiation and maintained low levels of SIRT1 expression in differentiated tissues. Specifically, miR-181a and b, miR-9, miR-204, miR-199b, and miR-135a suppressed SIRT1 protein expression. Inhibition of mir-9, the SIRT1-targeting miRNA induced earliest during mESC differentiation, prevented SIRT1 downregulation. Conversely, SIRT1 protein levels were upregulated post-transcriptionally during the reprogramming of mouse embryonic fibroblasts (MEFs) into induced pluripotent stem (iPS) cells. The regulation of SIRT1 protein levels by miRNAs might provide new opportunities for therapeutic tissue-specific modulation of SIRT1 expression and for reprogramming of somatic cells into iPS cells.