Intrachromosomal Looping Is Required for Activation of Endogenous Pluripotency Genes during Reprogramming
Intrachromosomal Looping Is Required for Activation of Endogenous Pluripotency Genes during Reprogramming
复制标题
重编程过程中内源多能性基因的激活需要染色体内环化。
DOI：
10.1016/j.stem.2013.05.012
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发表时间：
2013-07-03
期刊：
影响因子：
23.9
通讯作者：
Hu, Ji-Fan
中科院分区：
文献类型：
--
作者：
Zhang, He;Jiao, Weiwei;Hu, Ji-Fan
通过特定的因子诱导多能干细胞的产生是一个极其低效的过程，因为有一个强大的表观遗传学障碍阻止细胞实现多能性。在这里，我们报道病毒表达的因子在IPSCs和未重编程细胞(URCs)中以相同的程度与其目标基因的启动子结合。然而，内源性多能基因仅在IPSCs中表达。对OCT4基因局部染色质结构的比较表明，存在一个粘附素复合体介导的染色体内环，该环将下游的增强子并列到基因的启动子上，从而激活内源干细胞基因。在URC中没有观察到这些长程相互作用。RNAi敲除粘附素复合体基因SMC1后，染色体内相互作用消失，多能性受到影响。这些发现突显了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。
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.