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. STEM Cells2013;31:1278-1286

通过过表达一组特定的转录因子将体细胞重编程为诱导多能干细胞（iPSCs）需要多能性基因发生表观遗传变化。细胞核重编程是一个低效的过程，在iPSC产生过程中重置表观遗传状态的分子机制在很大程度上是未知的。在此，我们表明核小体重塑和去乙酰化（NuRD）复合物的下调对于高效重编程是必需的。NuRD的一个亚基Mbd3的过表达通过形成异染色质特征并沉默胚胎干细胞特异性标记基因（包括Oct4和Nanog）来抑制iPSCs的诱导。另一方面，Mbd3的缺失提高了重编程效率，并促进了多能干细胞的形成，即使在没有c - Myc或Sox2的情况下，这些多能干细胞也能够产生有活力的嵌合小鼠。这些结果确定Mbd3/NuRD是一种重要的表观遗传调节因子，它限制了关键多能性基因的表达，这表明药物诱导的Mbd3/NuRD下调可能是提高重编程效率和准确性的一种有力手段。《干细胞》2013年；31卷：1278 - 1286页