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Stem Cell文章:NuRD能阻断小鼠体细胞重新编程为多能干细胞

过表达一组特定转录因子从而将体细胞重新编程为诱导性多能干细胞的过程需要多能性基因的表观修饰改变。细胞和重编程是一个低效率的过程,iPSC产生过程中表观修饰状态重新设定的分子机制大部分仍属未知。北京大学深圳研究生院的研究者发现核小体重塑和去乙酰化复合体(nucleosome remodeling and deacetylation, NuRD)的功能下调对于有效进行重编程是必需的。上调NuRD的一个Mbd3亚单位的表达就能够建立异染色质状态并使得胚胎干细胞特异性标志物,如Oct4和Nanog的表达呈现静息状态,从而抑制iPSC的形成过程。而另一方面,敲除Mbd3则能提高重编程效率,促进多能干细胞形成并建立嵌合性小鼠,甚至不需要c-Myc和Sox2的存在。这些研究结果说明Mbd3/NuRD是重要的表观修饰调控者,它能够抑制关键的多能性基因的表达,如果通过药物下调Mbd3/NuRD功能可能对促进重编程效率和可靠性具有重要价值。该研究已经发表在2013年Stem Cell杂志上。本研究中小鼠基因表达谱检测工作由博奥生物集团有限公司完成。


原文摘要:
NuRD Blocks Reprogramming of Mouse Somatic Cells into Pluripotent Stem Cells
Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) by overexpression of a defined set of transcription factors requires epigenetic changes in pluripotency genes. Nuclear reprogramming is an inefficient process and the molecular mechanisms that reset the epigenetic state during iPSC generation are largely unknown. Here, we show that downregulation of the nucleosome remodeling and deacetylation (NuRD) complex is required for efficient reprogramming. Overexpression of Mbd3, a subunit of NuRD, inhibits induction of iPSCs by establishing heterochromatic features and silencing embryonic stem cell-specific marker genes, including Oct4 and Nanog. Depletion of Mbd3, on the other hand, improves reprogramming efficiency and facilitates the formation of pluripotent stem cells that are capable of generating viable chimeric mice, even in the absence of c-Myc or Sox2. The results establish Mbd3/NuRD as an important epigenetic regulator that restricts the expression of key pluripotency genes, suggesting that drug-induced downregulation of Mbd3/NuRD may be a powerful means to improve the efficiency and fidelity of reprogramming.
原文出处:
http://onlinelibrary.wiley.com/doi/10.1002/stem.1374/abstract