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 Rhee & 6 others Christine A. Wells, Thomas Preiss, Sean M. Grimmond, Ian M. Rogers, Andras Nagy, Jeong Sun Seo

Research output: Contribution to journalArticleResearchpeer-review

62 Citations (Scopus)

Abstract

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
Number of pages10
JournalNature Communications
Volume5
DOIs
Publication statusPublished - 10 Dec 2014
Externally publishedYes

Keywords

  • DNA methylation
  • pluripotency
  • reprogramming

Cite this

Lee, D. S., Shin, J. Y., Tonge, P. D., Puri, M. C., Lee, S., Park, H., ... Seo, J. S. (2014). An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator. Nature Communications, 5, [5619]. https://doi.org/10.1038/ncomms6619
Lee, Dong Sung ; Shin, Jong Yeon ; Tonge, Peter D. ; Puri, Mira C. ; Lee, Seungbok ; Park, Hansoo ; Lee, Won Chul ; Hussein, Samer M.I. ; Bleazard, Thomas ; Yun, Ji Young ; Kim, Jihye ; Li, Mira ; Cloonan, Nicole ; Wood, David ; Clancy, Jennifer L. ; Mosbergen, Rowland ; Yi, Jae Hyuk ; Yang, Kap Seok ; Kim, Hyungtae ; Rhee, Hwanseok ; Wells, Christine A. ; Preiss, Thomas ; Grimmond, Sean M. ; Rogers, Ian M. ; Nagy, Andras ; Seo, Jeong Sun. / An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator. In: Nature Communications. 2014 ; Vol. 5.
@article{e080e537087c423cbfaf6260d3053314,
title = "An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator",
abstract = "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.",
keywords = "DNA methylation, pluripotency, reprogramming",
author = "Lee, {Dong Sung} and Shin, {Jong Yeon} and Tonge, {Peter D.} and Puri, {Mira C.} and Seungbok Lee and Hansoo Park and Lee, {Won Chul} and Hussein, {Samer M.I.} and Thomas Bleazard and Yun, {Ji Young} and Jihye Kim and Mira Li and Nicole Cloonan and David Wood and Clancy, {Jennifer L.} and Rowland Mosbergen and Yi, {Jae Hyuk} and Yang, {Kap Seok} and Hyungtae Kim and Hwanseok Rhee and Wells, {Christine A.} and Thomas Preiss and Grimmond, {Sean M.} and Rogers, {Ian M.} and Andras Nagy and Seo, {Jeong Sun}",
year = "2014",
month = "12",
day = "10",
doi = "10.1038/ncomms6619",
language = "English",
volume = "5",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

Lee, DS, Shin, JY, Tonge, PD, Puri, MC, Lee, S, Park, H, Lee, WC, Hussein, SMI, Bleazard, T, Yun, JY, Kim, J, Li, M, Cloonan, N, Wood, D, Clancy, JL, Mosbergen, R, Yi, JH, Yang, KS, Kim, H, Rhee, H, Wells, CA, Preiss, T, Grimmond, SM, Rogers, IM, Nagy, A & Seo, JS 2014, 'An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator', Nature Communications, vol. 5, 5619. https://doi.org/10.1038/ncomms6619

An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator. / Lee, Dong Sung; Shin, Jong Yeon; Tonge, Peter D.; Puri, Mira C.; Lee, Seungbok; Park, Hansoo; Lee, Won Chul; Hussein, Samer M.I.; Bleazard, Thomas; Yun, Ji Young; Kim, Jihye; Li, Mira; Cloonan, Nicole; Wood, David; Clancy, Jennifer L.; Mosbergen, Rowland; Yi, Jae Hyuk; Yang, Kap Seok; Kim, Hyungtae; Rhee, Hwanseok; Wells, Christine A.; Preiss, Thomas; Grimmond, Sean M.; Rogers, Ian M.; Nagy, Andras; Seo, Jeong Sun.

In: Nature Communications, Vol. 5, 5619, 10.12.2014.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - An epigenomic roadmap to induced pluripotency reveals DNA methylation as a reprogramming modulator

AU - Lee, Dong Sung

AU - Shin, Jong Yeon

AU - Tonge, Peter D.

AU - Puri, Mira C.

AU - Lee, Seungbok

AU - Park, Hansoo

AU - Lee, Won Chul

AU - Hussein, Samer M.I.

AU - Bleazard, Thomas

AU - Yun, Ji Young

AU - Kim, Jihye

AU - Li, Mira

AU - Cloonan, Nicole

AU - Wood, David

AU - Clancy, Jennifer L.

AU - Mosbergen, Rowland

AU - Yi, Jae Hyuk

AU - Yang, Kap Seok

AU - Kim, Hyungtae

AU - Rhee, Hwanseok

AU - Wells, Christine A.

AU - Preiss, Thomas

AU - Grimmond, Sean M.

AU - Rogers, Ian M.

AU - Nagy, Andras

AU - Seo, Jeong Sun

PY - 2014/12/10

Y1 - 2014/12/10

N2 - 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.

AB - 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.

KW - DNA methylation

KW - pluripotency

KW - reprogramming

UR - http://www.scopus.com/inward/record.url?scp=84923368892&partnerID=8YFLogxK

U2 - 10.1038/ncomms6619

DO - 10.1038/ncomms6619

M3 - Article

VL - 5

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 5619

ER -