Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways.
Sirtuin 1 facilitates generation of induced pluripotent stem cells from mouse embryonic fibroblasts through the miR-34a and p53 pathways.
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DOI：
10.1371/journal.pone.0045633
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yeung WS
中科院分区：
文献类型：
--
作者：
Lee YL;Peng Q;Fong SW;Chen AC;Lee KF;Ng EH;Nagy A;Yeung WS
转录因子的强制表达可以将体细胞重编程为诱导多能干细胞（iPSC）。最近的研究表明，可以通过包含调节染色质修饰酶的小分子来提高重编程效率。我们在这里报道sirtuin 1 (SIRT1)， NAD+依赖性蛋白去乙酰化酶sirtuin家族的成员，参与iPSC的形成。通过使用一种高效的小鼠次级成纤维细胞重编程系统，使用多西环素（DOX）诱导的Yamanaka转录因子通过piggyBac （PB）转位传递（2°F/1B MEF），我们发现SIRT1敲低降低，而白藜芦醇（RSV）增加了iPSC形成的效率。这些处理与乙酰化p53及其下游Nanog的改变有关，但与p21的表达无关。SIRT1过表达也证实了这种刺激作用，诱导Nanog刺激了菌落的形成，降低了p21的表达。此外，RSV和SIRT1敲低对重编程的影响在重编程的起始阶段最为明显。MicroRNA-34a是已知的SIRT1调控因子。其抑制剂增加，而其模拟物减少iPSC的形成。SIRT1在重编程过程中的刺激作用也在原发性MEF中得到证实。当tenovin-6（一种通过SIRT1抑制激活p53的小分子）抑制重编程时，RSV增加。综上所述，SIRT1促进iPSC的生成，部分是通过p53的去乙酰化、p21的抑制和Nanog表达的增强。
Forced-expression of transcription factors can reprogram somatic cells into induced pluripotent stem cells (iPSC). Recent studies show that the reprogramming efficiency can be improved by inclusion of small molecules that regulate chromatin modifying enzymes. We report here that sirtuin 1 (SIRT1), a member of the sirtuin family of NAD+-dependent protein deacetylases, is involved in iPSC formation. By using an efficient mouse secondary fibroblast reprogramming system with doxycycline (DOX) inducible Yamanaka’s transcription factors delivered by piggyBac (PB) transposition (2°F/1B MEF), we show that SIRT1 knockdown decreased while resveratrol (RSV) increased the efficiency of iPSC formation. The treatments were associated with altered acetylated p53 and its downstream Nanog but not p21 expression. The stimulatory effect was also confirmed by SIRT1 over-expression, which stimulated the formation of colonies with induced Nanog and reduced p21 expression. Furthermore, the effects of RSV and SIRT1 knockdown on reprogramming were most pronounced during the initiation phase of reprogramming. MicroRNA-34a is a known regulator of SIRT1. Its inhibitor increased, while its mimics reduced iPSC formation. The stimulatory effect of SIRT1 during reprogramming was also confirmed in the primary MEF. RSV increased while tenovin-6, a small molecule that activates p53 through SIRT1 inhibition, suppressed reprogramming. In conclusion, SIRT1 enhances iPSC generation, in part, through deacetylation of p53, inhibition of p21 and enhancement of Nanog expression.
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