Regulation of DNA methylation landscape in human somatic cell reprogramming by miR-29 family (RNA-seq)

Reprogramming to pluripotency after overexpression of OCT4, SOX2, KLF4 and MYC is accompanied by global genomic and epigenomic changes. Histone modification and DNA methylation states in iPSCs have been shown to be highly similar with embryonic stem cells (ESCs). However, epigenetic differences still exist between iPSCs and ESCs. In particular, aberrant DNA methylation states found in iPSCs are a major concern for using iPSCs in a clinical setting. Thus, it is critical to find factors that regulate DNA methylation states in reprogramming. Here, we found that the miR-29 family is an important epigenetic regulator during human somatic cell reprogramming. Our global DNA methylation and hydroxymethylation analysis shows that DNA demethylation is a major event mediated by miR-29a depletion during early reprogramming, and that iPSCs derived from miR-29a depletion are epigenetically closer to ESCs. Our findings uncover an important miRNA-based approach to generate clinically robust iPSCs. Overall design: Bisulphite converted gDNAs of D551 fibroblasts transduced for 3 days with overexpression of DNMTs, TETs, TDG and OSKM or miR29a/b/c and control sponge were hybridized into Illumina Infinium HumanMethylation 450K Beadchip.

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Hysolli E, Tanaka Y, Su J, Kim KY, Zhong T, Janknecht R, Zhou XL, Geng L, Qiu C, Pan X, Jung YW, Cheng J, Lu J, Zhong M, Weissman SM, Park IH