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

Generation of induced pluripotent stem cells (iPSCs) depends on the synthesis of factor proteins that regulate the developmental clock of adult cells in order to return them to the embryonic state. However, the efficiency of iPSC induction is extremely low with all existing approaches. To fundamentally improve this technology, we examined the epigenetic barrier that limits the generation of iPSCs. We first compared the binding of these factors to their target gene promoters. It was surprised to find that these factors bound to their target promoters equally in both iPSCs and non-iPSCs. We then examined the local chromatin structure and found that the formation of chromatin loop is required for of nuclear remodeling in iPSCs. None of the chromatin loop was detected in non-iPSCs. The pluripotency-related loop juxtaposes the enhancer and promoter regions to reactivate target genes. We also identified chromatin factor SMC1 as the key molecule for organizing the enhancer/promoter loop. This study thus identifies chromatin looping as a key epigenetic barrier that affects iPSC induction. Thus, further studies should be focused on the identification of other factors that can organize chromatin loops in order to promote iPSC induction.