Department of Ophthalmology, Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai 200025, P.R. China.
Cell Stem Cell. 2013 Jul 3;13(1):30-5. doi: 10.1016/j.stem.2013.05.012. Epub 2013 Jun 6.
Generation of induced pluripotent stem cells (iPSCs) by defined factors is an extremely inefficient process, because there is a strong epigenetic block preventing cells from achieving pluripotency. Here we report that virally expressed factors bound to the promoters of their target genes to the same extent in both iPSCs and unreprogrammed cells (URCs). However, expression of endogenous pluripotentcy genes was observed only in iPSCs. Comparison of local chromatin structure of the OCT4 locus revealed that there was a cohesin-complex-mediated intrachromosomal loop that juxtaposes a downstream enhancer to the gene's promoter, enabling activation of endogenous stemness genes. None of these long-range interactions were observed in URCs. Knockdown of the cohesin-complex gene SMC1 by RNAi abolished the intrachromosomal interaction and affected pluripotency. These findings highlight the importance of the SMC1-orchestrated intrachromosomal loop as a critical epigenetic barrier to the induction of pluripotency.
通过定义因子生成诱导多能干细胞（iPSCs）是一个极其低效的过程，因为存在强烈的表观遗传阻断，阻止细胞获得多能性。在这里，我们报告说，病毒表达的因子与它们的靶基因的启动子结合的程度在 iPSCs 和未重编程细胞（URCs）中是相同的。然而，内源性多能性基因的表达仅在 iPSCs 中观察到。对 OCT4 基因座局部染色质结构的比较表明，存在一个由黏合蛋白复合物介导的染色体内环，将下游增强子与基因的启动子并列，从而激活内源性干性基因。在 URCs 中没有观察到这些长距离相互作用。通过 RNAi 敲低黏合蛋白复合物基因 SMC1 会破坏染色体内相互作用并影响多能性。这些发现强调了 SMC1 协调的染色体内环作为诱导多能性的关键表观遗传障碍的重要性。
