H3K9 methylation is a barrier during somatic cell reprogramming into iPSCs

被引：392

作者：

Chen, Jiekai ^{[1
,2
]}

Liu, He ^{[1
,2
]}

Liu, Jing ^{[1
,2
]}

Qi, Jing ^{[1
,2
]}

Wei, Bei ^{[1
,2
]}

Yang, Jiaqi ^{[1
,2
]}

Liang, Hanquan ^{[1
,2
]}

Chen, You ^{[1
,2
]}

Chen, Jing ^{[1
,2
]}

Wu, Yaran ^{[1
,2
]}

Guo, Lin ^{[1
,2
]}

Zhu, Jieying ^{[1
,2
]}

Zhao, Xiangjie ^{[1
,2
]}

Peng, Tianran ^{[1
,2
]}

Zhang, Yixin ^{[1
,2
]}

Chen, Shen ^{[1
,2
]}

Li, Xuejia ^{[1
,2
]}

Li, Dongwei ^{[1
,2
]}

Wang, Tao ^{[1
,2
]}

Pei, Duanqing ^{[1
,2
]}

机构：

[1] Chinese Acad Sci, Key Lab Regenerat Biol, S China Inst Stem Cell Biol & Regenerat Med, Guangzhou Inst Biomed & Hlth, Guangzhou, Guangdong, Peoples R China

[2] Chinese Acad Sci, Guangdong Prov Key Lab Stem Cell & Regenerat Med, S China Inst Stem Cell Biol & Regenerat Med, Guangzhou Inst Biomed & Hlth, Guangzhou, Guangdong, Peoples R China

来源：

NATURE GENETICS | 2013年 / 45卷 / 01期

基金：

中国国家自然科学基金;

关键词：

PLURIPOTENT STEM-CELLS; SELF-RENEWAL; FIBROBLASTS; INDUCTION; GENERATION; KLF4;

D O I：

10.1038/ng.2491

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

The induction of pluripotent stem cells (iPSCs) by defined factors is poorly understood stepwise. Here, we show that histone H3 lysine 9 (H3K9) methylation is the primary epigenetic determinant for the intermediate pre-iPSC state, and its removal leads to fully reprogrammed iPSCs. We generated a panel of stable pre-iPSCs that exhibit pluripotent properties but do not activate the core pluripotency network, although they remain sensitive to vitamin C for conversion into iPSCs. Bone morphogenetic proteins (BMPs) were subsequently identified in serum as critical signaling molecules in arresting reprogramming at the pre-iPSC state. Mechanistically, we identified H3K9 methyltransferases as downstream targets of BMPs and showed that they function with their corresponding demethylases as the on/off switch for the pre-iPSC fate by regulating H3K9 methylation status at the core pluripotency loci. Our results not only establish pre-iPSCs as an epigenetically stable signpost along the reprogramming road map, but they also provide mechanistic insights into the epigenetic reprogramming of cell fate.

引用

页码：34 / U62

页数：10

共 39 条

[1] Wdr5 Mediates Self-Renewal and Reprogramming via the Embryonic Stem Cell Core Transcriptional Network [J].

Ang, Yen-Sin ;

Tsai, Su-Yi ;

Lee, Dung-Fang ;

Monk, Jonathan ;

Su, Jie ;

Ratnakumar, Kajan ;

Ding, Junjun ;

Ge, Yongchao ;

Darr, Henia ;

Chang, Betty ;

Wang, Jianlong ;

Rendl, Michael ;

Bernstein, Emily ;

Schaniel, Christoph ;

Lemischka, Ihor R. .

CELL, 2011, 145 (02) :183-197

[2] Epigenetic Memory and Preferential Lineage-Specific Differentiation in Induced Pluripotent Stem Cells Derived from Human Pancreatic Islet Beta Cells [J].

Bar-Nur, Ori ;

Russ, Holger A. ;

Efrat, Shimon ;

Benvenisty, Nissim .

CELL STEM CELL, 2011, 9 (01) :17-23

[3] BMPs functionally replace Klf4 and support efficient reprogramming of mouse fibroblasts by Oct4 alone [J].

Chen, Jiekai ;

Liu, Jing ;

Yang, Jiaqi ;

Chen, You ;

Chen, Jing ;

Ni, Su ;

Song, Hong ;

Zeng, Lingwen ;

Ding, Ke ;

Pei, Duanqing .

CELL RESEARCH, 2011, 21 (01) :205-212

[4] Towards an Optimized Culture Medium for the Generation of Mouse Induced Pluripotent Stem Cells [J].

Chen, Jiekai ;

Liu, Jing ;

Han, Qingkai ;

Qin, Dajiang ;

Xu, Jianyong ;

Chen, You ;

Yang, Jiaqi ;

Song, Hong ;

Yang, Dongshan ;

Peng, Meixiu ;

He, Wenzhi ;

Li, Ronghui ;

Wang, Hao ;

Gan, Yi ;

Ding, Ke ;

Zeng, Lingwen ;

Lai, Liangxue ;

Esteban, Miguel A. ;

Pei, Duanqing .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (40) :31066-31072

[5] BMP Signaling in the Human Fetal Ovary is Developmentally Regulated and Promotes Primordial Germ Cell Apoptosis [J].

Childs, Andrew J. ;

Kinnell, Hazel L. ;

Collins, Craig S. ;

Hogg, Kirsten ;

Bayne, Rosemary A. L. ;

Green, Samira J. ;

McNeilly, Alan S. ;

Anderson, Richard A. .

STEM CELLS, 2010, 28 (08) :1368-1378

[6] Bone morphogenetic protein-9 is a circulating vascular quiescence factor [J].

David, Laurent ;

Mallet, Christine ;

Keramidas, Michelle ;

Lamande, Noel ;

Gasc, Jean-Marie ;

Dupuis-Girod, Sophie ;

Plauchu, Henri ;

Feige, Jean-Jacques ;

Bailly, Sabine .

CIRCULATION RESEARCH, 2008, 102 (08) :914-922

[7] Vitamin C Enhances the Generation of Mouse and Human Induced Pluripotent Stem Cells [J].

Esteban, Miguel Angel ;

Wang, Tao ;

Qin, Baoming ;

Yang, Jiayin ;

Qin, Dajiang ;

Cai, Jinglei ;

Li, Wen ;

Weng, Zhihui ;

Chen, Jiekai ;

Ni, Su ;

Chen, Keshi ;

Li, Yuan ;

Liu, Xiaopeng ;

Xu, Jianyong ;

Zhang, Shiqiang ;

Li, Feng ;

He, Wenzhi ;

Labuda, Krystyna ;

Song, Yancheng ;

Peterbauer, Anja ;

Wolbank, Susanne ;

Redl, Heinz ;

Zhong, Mei ;

Cai, Daozhang ;

Zeng, Lingwen ;

Pei, Duanqing .

CELL STEM CELL, 2010, 6 (01) :71-79

[8] Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb [J].

Feng, Bo ;

Jiang, Jianming ;

Kraus, Petra ;

Ng, Jia-Hui ;

Heng, Jian-Chien Dominic ;

Chan, Yun-Shen ;

Yaw, Lai-Ping ;

Zhang, Weiwei ;

Loh, Yuin-Han ;

Han, Jianyong ;

Vega, Vinsensius B. ;

Cacheux-Rataboul, Valere ;

Lim, Bing ;

Lufkin, Thomas ;

Ng, Huck-Hui .

NATURE CELL BIOLOGY, 2009, 11 (02) :197-U193

[9] A Subset of the Histone H3 Lysine 9 Methyltransferases Suv39h1, G9a, GLP, and SETDB1 Participate in a Multimeric Complex [J].

Fritsch, Lauriane ;

Robin, Philippe ;

Mathieu, Jacques R. R. ;

Souidi, Mouloud ;

Hinaux, Helene ;

Rougeulle, Claire ;

Harel-Bellan, Annick ;

Ameyar-Zazoua, Maya ;

Ait-Si-Ali, Slimane .

MOLECULAR CELL, 2010, 37 (01) :46-56

[10] Suv39h histone methyltransferases interact with Smads and cooperate in BMP-induced repression [J].

Frontelo, P ;

Leader, JE ;

Yoo, N ;

Potocki, AC ;

Crawford, M ;

Kulik, M ;

Lechleider, RJ .

ONCOGENE, 2004, 23 (30) :5242-5251

← 1 2 3 4 →