An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator

Dong Sung Lee, Jong Yeon Shin, Peter D. Tonge, Mira C. Puri, Seungbok Lee, Hansoo Park, Won Chul Lee, Samer M.I. Hussein, Thomas Bleazard, Ji Young Yun, Jihye Kim, Mira Li, Nicole Cloonan, David Wood, Jennifer L. Clancy, Rowland Mosbergen, Jae Hyuk Yi, Kap Seok Yang, Hyungtae Kim, Hwanseok RheeChristine A. Wells, Thomas Preiss, Sean M. Grimmond, Ian M. Rogers, Andras Nagy, Jeong Sun Seo

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91 Scopus citations


Reprogramming of somatic cells to induced pluripotent stem cells involves a dynamic rearrangement of the epigenetic landscape. To characterize this epigenomic roadmap, we have performed MethylC-seq, ChIP-seq (H3K4/K27/K36me3) and RNA-Seq on samples taken at several time points during murine secondary reprogramming as part of Project Grandiose. We find that DNA methylation gain during reprogramming occurs gradually, while loss is achieved only at the ESC-like state. Binding sites of activated factors exhibit focal demethylation during reprogramming, while ESC-like pluripotent cells are distinguished by extension of demethylation to the wider neighbourhood. We observed that genes with CpG-rich promoters demonstrate stable low methylation and strong engagement of histone marks, whereas genes with CpG-poor promoters are safeguarded by methylation. Such DNA methylation-driven control is the key to the regulation of ESC-pluripotency genes, including Dppa4, Dppa5a and Esrrb. These results reveal the crucial role that DNA methylation plays as an epigenetic switch driving somatic cells to pluripotency.

Original languageEnglish
Article number5619
JournalNature Communications
StatePublished - 2014


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