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Cell Stem Cell文章:Tet1在iPS细胞诱导过程中的作用

日期:2019/04/16  来源:新葡萄京娱乐场官方网站

  

  细胞重编程可以通过Oct4(O), Sox2(S),Klf4(K)和c-Myc(M)等转录因子的共同作用来实现。在传统的OSKM体系中,过表达DNA羟化酶Tet1(T)可以促进Oct4转录控制区内5-甲基胞嘧(5mC)转化为5-羟甲基胞嘧啶(5hmC),使Oct4发生去甲基化并激活其表达,从而促进了细胞重编程和诱导性多能干细胞(iPS细胞)的诱导。Tet1与SKM联用可以取代传统体系中最为重要的转录因子Oct4,并获得致癌风险更低的iPS细胞,提升了iPS细胞的安全性。本研究中,编辑建立了一套TSKM二次诱导体系,在分子水平研究小鼠纤维瘤细胞重编程至iPS细胞的过程。DNA的甲基化与去甲基化是细胞重编程过程中的重要因素,因此编辑采用高通量表达谱芯片研究了5mC与5hmC之间的动态变化对基因组转录调控的影响。Affymetrix Mouse Gene 1.0 ST Array检测服务北京新葡萄京娱乐场官方网站生物技术有限企业完成。本研究证明Tet1可以取代传统体系中的Oct4,实现安全高效的体细胞重编程。TSKM体系的建立为将来开展更深入的研究提供了有力的工具。本研究于2013年3月在线发表在Cell子刊《Cell Stem Cell》(影响因子:25.943)。


原文摘要:

  Replacement of Oct4 by Tet1 during iPSC Induction Reveals an Important Role of DNA Methylation and Hydroxymethylation in Reprogramming

  DNA methylation and demethylation have been proposed to play an important role in somatic cell reprogramming. Here, we demonstrate that the DNA hydroxylase Tet1 facilitates pluripotent stem cell induction by promoting Oct4 demethylation and reactivation. Moreover, Tet1 (T) can replace Oct4 and initiate somatic cell reprogramming in conjunction with Sox2 (S), Klf4 (K), and c-Myc (M). We established an efficient TSKM secondary reprogramming system and used it to characterize the dynamic profiles of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and gene expression during reprogramming. Our analysis revealed that both 5mC and 5hmC modifications increased at an intermediate stage of the process, correlating with a transition in the transcriptional profile. We also found that 5hmC enrichment is involved in the demethylation and reactivation of genes and regulatory regions that are important for pluripotency. Our data indicate that changes in DNA methylation and hydroxymethylation play important roles in genome-wide epigenetic remodeling during reprogramming.

 

原文出处:http://www.sciencedirect.com/science/article/pii/S193459091300060X

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