The Role of SIRT6 Protein in Aging and Reprogramming of Human Induced Pluripotent Stem Cells
The Role of SIRT6 Protein in Aging and Reprogramming of Human Induced Pluripotent Stem Cells
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DOI：
10.1074/jbc.m112.405928
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发表时间：
2013-06-21
影响因子：
4.8
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
--
作者：
Sharma, Amit;Diecke, Sebastian;Wu, Joseph C.
众所周知，衰老是多种疾病最重要的危险因素。Sirtuin 6，或SIRT6，最近被确定为转录、基因组稳定性、端粒完整性、DNA修复和代谢稳态的关键调节因子。SIRT6基因敲除小鼠模型显示出显著的加速衰老表型。与其在衰老中的作用保持一致，我们证明了来自老年人类受试者的人真皮成纤维细胞（HDFs）比来自年轻人类受试者的人真皮成纤维细胞更能抵抗经典山中因子的重编程，但在重编程过程中添加SIRT6大大提高了老年HDFs的这种效率。尽管SIRT6很重要，但对其调控的分子机制知之甚少。我们首次发现miR-766对SIRT6的转录后调控以及该microRNA在不同年龄组HDFs中的表达呈负相关。我们的研究结果表明，SIRT6通过反馈调节回路调节miR-766的转录，这对衰老细胞重编程中SIRT6表达的调节具有重要意义。
Aging is known to be the single most important risk factor for multiple diseases. Sirtuin 6, or SIRT6, has recently been identified as a critical regulator of transcription, genome stability, telomere integrity, DNA repair, and metabolic homeostasis. A knockout mouse model of SIRT6 has displayed dramatic phenotypes of accelerated aging. In keeping with its role in aging, we demonstrated that human dermal fibroblasts (HDFs) from older human subjects were more resistant to reprogramming by classic Yamanaka factors than those from younger human subjects, but the addition of SIRT6 during reprogramming improved such efficiency in older HDFs substantially. Despite the importance of SIRT6, little is known about the molecular mechanism of its regulation. We show, for the first, time posttranscriptional regulation of SIRT6 by miR-766 and inverse correlation in the expression of this microRNA in HDFs from different age groups. Our results suggest that SIRT6 regulates miR-766 transcription via a feedback regulatory loop, which has implications for the modulation of SIRT6 expression in reprogramming of aging cells.