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

被引：92

作者：

Lee, Dong-Sung ^{[1
,2
,3
]}

Shin, Jong-Yeon ^{[1
,4
]}

Tonge, Peter D. ^{[5
]}

Puri, Mira C. ^{[5
,6
]}

Lee, Seungbok ^{[1
,2
,3
]}

Park, Hansoo ^{[1
,2
,3
]}

Lee, Won-Chul ^{[1
,4
]}

Hussein, Samer M. I. ^{[5
]}

Bleazard, Thomas ^{[7
]}

Yun, Ji-Young ^{[1
,4
]}

Kim, Jihye ^{[1
,4
]}

Li, Mira ^{[5
]}

Cloonan, Nicole ^{[8
,9
]}

Wood, David ^{[8
]}

Clancy, Jennifer L. ^{[10
]}

Mosbergen, Rowland ^{[11
]}

Yi, Jae-Hyuk ^{[1
]}

Yang, Kap-Seok ^{[4
]}

Kim, Hyungtae ^{[4
]}

Rhee, Hwanseok ^{[12
]}

Wells, Christine A. ^{[11
,13
]}

Preiss, Thomas ^{[10
,14
]}

Grimmond, Sean M. ^{[8
,15
]}

Rogers, Ian M. ^{[5
,16
,17
]}

Nagy, Andras ^{[5
,17
,18
]}

Seo, Jeong-Sun ^{[1
,2
,3
,4
]}

机构：

[1] Seoul Natl Univ, Med Res Ctr, GMI, Seoul 110799, South Korea

[2] Seoul Natl Univ, Coll Med, Dept Biomed Sci, Seoul 110799, South Korea

[3] Seoul Natl Univ, Coll Med, Dept Biochem, Seoul 110799, South Korea

[4] Macrogen Inc, Inst Life Sci, Seoul 153781, South Korea

[5] Mt Sinai Hosp, Lunenfeld Tanenbaum Res Inst, Toronto, ON M5G 1X5, Canada

[6] Univ Toronto, Dept Med Biophys, Toronto, ON M5T 3H7, Canada

[7] Univ Manchester, Fac Med & Human Sci, Manchester M13 9PT, Lancs, England

[8] Univ Queensland, Queensland Ctr Med Genom, Inst Mol Biosci, St Lucia, Qld 4072, Australia

[9] QIMR Berghofer Med Res Inst, Genom Biol Lab, Herston, Qld 4006, Australia

[10] Australian Natl Univ, John Curtin Sch Med Res, Genome Biol Dept, Canberra, ACT 2601, Australia

[11] Univ Queensland, Australian Inst Bioengn & Nanotechnol, Brisbane, Qld 4072, Australia

[12] Macrogen, Macrogen Bioinformat Ctr, Seoul 153781, South Korea

[13] Univ Glasgow, Coll Med Vet & Life Sci, Glasgow G12 8TA, Lanark, Scotland

[14] Victor Chang Cardiac Res Inst, Mol Struct & Computat Biol Div, Sydney, NSW 2010, Australia

[15] Univ Glasgow, WolfsonWohl Canc Res Ctr, Inst Canc Sci, Glasgow G61 1BD, Lanark, Scotland

[16] Univ Toronto, Dept Physiol, Toronto, ON M5T 3H7, Canada

[17] Univ Toronto, Dept Obstet & Gynaecol, Toronto, ON M5T 3H7, Canada

[18] Univ Toronto, Inst Med Sci, Toronto, ON M5T 3H7, Canada

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

关键词：

BINDING SITES; SOMATIC-CELLS; STEM-CELLS; FIBROBLASTS; CHROMATIN;

D O I：

10.1038/ncomms6619

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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