Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Transgenic Mice Unit, Biotechnology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Stem Cell Reports. 2014 Apr 17;2(5):690-706. doi: 10.1016/j.stemcr.2014.03.002. eCollection 2014 May 6.
The NAD-dependent deacetylase SIRT1 is involved in chromatin silencing and genome stability. Elevated SIRT1 levels in embryonic stem cells also suggest a role for SIRT1 in pluripotency. Murine SIRT1 attenuates telomere attrition in vivo and is recruited at telomeres in induced pluripotent stem cells (iPSCs). Because telomere elongation is an iPSC hallmark, we set out to study the role of SIRT1 in pluripotency in the setting of murine embryonic fibroblasts reprogramming into iPSCs. We find that SIRT1 is required for efficient postreprogramming telomere elongation, and that this effect is mediated by a c-MYC-dependent regulation of the mTert gene. We further demonstrate that SIRT1-deficient iPSCs accumulate chromosomal aberrations and show a derepression of telomeric heterochromatin. Finally, SIRT1-deficient iPSCs form larger teratomas that are poorly differentiated, highlighting a role for SIRT1 in exit from pluripotency. In summary, this work demonstrates a role for SIRT1 in the maintenance of pluripotency and modulation of differentiation.
NAD 依赖性去乙酰化酶 SIRT1 参与染色质沉默和基因组稳定性。胚胎干细胞中 SIRT1 水平的升高也表明 SIRT1 在多能性中起作用。鼠 SIRT1 减弱体内端粒磨损，并在诱导多能干细胞（iPSCs）中募集到端粒。因为端粒延长是 iPSC 的标志，我们着手研究 SIRT1 在鼠胚胎成纤维细胞重编程为 iPSCs 时在多能性中的作用。我们发现 SIRT1 是高效的重编程后端粒延长所必需的，并且这种效应是通过 c-MYC 依赖调节 mTert 基因来介导的。我们进一步证明，SIRT1 缺陷型 iPSCs 积累染色体异常，并显示端粒异染色质去抑制。最后，SIRT1 缺陷型 iPSCs 形成更大的畸胎瘤，分化不良，突出了 SIRT1 在退出多能性中的作用。总之，这项工作证明了 SIRT1 在维持多能性和调节分化中的作用。
