Intrachromosomal Looping Is Required for Activation of Endogenous Pluripotency Genes during Reprogramming.

Cell Stem Cell
Publication Year: 
He Zhang
Weiwei Jiao
Lin Sun
Jiayan Fan
Mengfei Chen
Hong Wang
Xiaoyi Xu
Adong Shen
Tao Li
Beibei Niu
Shengfang Ge
Wei Li
Jiuwei Cui
Guanjun Wang
Jingnan Sun
Xianqun Fan
Xiang Hu
Randall J Mrsny
Andrew R Hoffman
Ji-Fan Hu
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Public Summary: 
Scientific Abstract: 
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.