Nature2014-06-26 2:14 PM

iPS细胞的快速高效生成 C/EBPα poises B cells for rapid reprogramming into induced pluripotent stem cells

论文摘要 

Thomas Graf及同事所做的一项新的研究,描述了在Yamanaka ‘OSKM’重新编程因子的过度表达之后C/EBP/ (转录因子CCAAT/增强子结合蛋白--)的一个脉冲怎样导致B-细胞前体被快速地、非常高效地重新编程为“诱导多能干”(iPS)细胞。作者发现,C/EBP/使染色质更易接近,通过一个涉及Tet2酶的活化的机制加快多能性基因的表达。关于B-细胞被高效、快速重新编程为iPS细胞的这一发现,为重新编程过程的研究提供了一个模型,同时也可能会具有临床意义。

Abstract 

CCAAT/enhancer binding protein-α (C/EBPα) induces transdifferentiation of B cells into macrophages at high efficiencies and enhances reprogramming into induced pluripotent stem (iPS) cells when co-expressed with the transcription factors Oct4 (Pou5f1), Sox2, Klf4 and Myc (hereafter called OSKM). However, how C/EBPα accomplishes these effects is unclear. Here we find that in mouse primary B cells transient C/EBPα expression followed by OSKM activation induces a 100-fold increase in iPS cell reprogramming efficiency, involving 95% of the population. During this conversion, pluripotency and epithelial–mesenchymal transition genes become markedly upregulated, and 60% of the cells express Oct4 within 2 days. C/EBPα acts as a ‘path-breaker’ as it transiently makes the chromatin of pluripotency genes more accessible to DNase I. C/EBPα also induces the expression of the dioxygenase Tet2 and promotes its translocation to the nucleus where it binds to regulatory regions of pluripotency genes that become demethylated after OSKM induction. In line with these findings, overexpression of Tet2 enhances OSKM-induced B-cell reprogramming. Because the enzyme is also required for efficient C/EBPα-induced immune cell conversion3, our data indicate that Tet2 provides a mechanistic link between iPS cell reprogramming and B-cell transdifferentiation. The rapid iPS reprogramming approach described here should help to fully elucidate the process and has potential clinical applications.

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