OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells

被引:103
作者
Navarro, Pablo [1 ]
Festuccia, Nicola [1 ]
Colby, Douglas [1 ]
Gagliardi, Alessia [1 ]
Mullin, Nicholas P. [1 ]
Zhang, Wensheng [1 ]
Karwacki-Neisius, Violetta [1 ]
Osorno, Rodrigo [1 ]
Kelly, David [2 ]
Robertson, Morag [1 ]
Chambers, Ian [1 ]
机构
[1] Univ Edinburgh, Sch Biol Sci, Inst Stem Cell Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland
[2] Univ Edinburgh, Sch Biol Sci, Wellcome Trust Ctr Cell Biol, Ctr Opt Instrumentat Lab, Edinburgh EH16 4UU, Midlothian, Scotland
基金
英国惠康基金; 英国医学研究理事会;
关键词
heterogeneity; nanog; network; pluripotency; self-renewal; EMBRYONIC STEM-CELLS; GROUND-STATE PLURIPOTENCY; SELF-RENEWAL; TRANSCRIPTIONAL NETWORK; PRIMITIVE ENDODERM; SIGNALING PATHWAYS; OCT4; DIFFERENTIATION; NOISE; INTERACTS;
D O I
10.1038/emboj.2012.321
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
NANOG, OCT4 and SOX2 form the core network of transcription factors supporting embryonic stem (ES) cell self-renewal. While OCT4 and SOX2 expression is relatively uniform, ES cells fluctuate between states of high NANOG expression possessing high self-renewal efficiency, and low NANOG expression exhibiting increased differentiation propensity. NANOG, OCT4 and SOX2 are currently considered to activate transcription of each of the three genes, an architecture that cannot readily account for NANOG heterogeneity. Here, we examine the architecture of the Nanog-centred network using inducible NANOG gain- and loss-of-function approaches. Rather than activating itself, Nanog activity is autorepressive and OCT4/SOX2-independent. Moreover, the influence of Nanog on Oct4 and Sox2 expression is minimal. Using Nanog:GFP reporters, we show that Nanog autorepression is a major regulator of Nanog transcription switching. We conclude that the architecture of the pluripotency gene regulatory network encodes the capacity to generate reversible states of Nanog transcription via a Nanog-centred autorepressive loop. Therefore, cellular variability in self-renewal efficiency is an emergent property of the pluripotency gene regulatory network. The EMBO Journal (2012) 31, 4547-4562. doi: 10.1038/emboj.2012.321; Published online 23 November 2012
引用
收藏
页码:4547 / 4562
页数:16
相关论文
共 43 条
[1]   Cellular Decision Making and Biological Noise: From Microbes to Mammals [J].
Balazsi, Gabor ;
van Oudenaarden, Alexander ;
Collins, James J. .
CELL, 2011, 144 (06) :910-925
[2]   Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells [J].
Chambers, I ;
Colby, D ;
Robertson, M ;
Nichols, J ;
Lee, S ;
Tweedie, S ;
Smith, A .
CELL, 2003, 113 (05) :643-655
[3]   Nanog safeguards pluripotency and mediates germline development [J].
Chambers, Ian ;
Silva, Jose ;
Colby, Douglas ;
Nichols, Jennifer ;
Nijmeijer, Bianca ;
Robertson, Morag ;
Vrana, Jan ;
Jones, Ken ;
Grotewold, Lars ;
Smith, Austin .
NATURE, 2007, 450 (7173) :1230-U8
[4]   Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway [J].
Chazaud, Claire ;
Yamanaka, Yojiro ;
Pawson, Tony ;
Rossant, Janet .
DEVELOPMENTAL CELL, 2006, 10 (05) :615-624
[5]   Integration of external signaling pathways with the core transcriptional network in embryonic stem cells [J].
Chen, Xi ;
Xu, Han ;
Yuan, Ping ;
Fang, Fang ;
Huss, Mikael ;
Vega, Vinsensius B. ;
Wong, Eleanor ;
Orlov, Yuriy L. ;
Zhang, Weiwei ;
Jiang, Jianming ;
Loh, Yuin-Han ;
Yeo, Hock Chuan ;
Yeo, Zhen Xuan ;
Narang, Vipin ;
Govindarajan, Kunde Ramamoorthy ;
Leong, Bernard ;
Shahab, Atif ;
Ruan, Yijun ;
Bourque, Guillaume ;
Sung, Wing-Kin ;
Clarke, Neil D. ;
Wei, Chia-Lin ;
Ng, Huck-Hui .
CELL, 2008, 133 (06) :1106-1117
[6]   Stochastic patterning in the mouse pre-implantation embryo [J].
Dietrich, Jens-Erik ;
Hiiragi, Takashi .
DEVELOPMENT, 2007, 134 (23) :4219-4231
[7]   Esrrb Is a Direct Nanog Target Gene that Can Substitute for Nanog Function in Pluripotent Cells [J].
Festuccia, Nicola ;
Osorno, Rodrigo ;
Halbritter, Florian ;
Karwacki-Neisius, Violetta ;
Navarro, Pablo ;
Colby, Douglas ;
Wong, Frederick ;
Yates, Adam ;
Tomlinson, Simon R. ;
Chambers, Ian .
CELL STEM CELL, 2012, 11 (04) :477-490
[8]   Zfp281 mediates Nanog autorepression through recruitment of the NuRD complex and inhibits somatic cell reprogramming [J].
Fidalgo, Miguel ;
Faiola, Francesco ;
Pereira, Carlos-Filipe ;
Ding, Junjun ;
Saunders, Arven ;
Gingold, Julian ;
Schaniel, Christoph ;
Lemischka, Ihor R. ;
Silva, Jose C. R. ;
Wang, Jianlong .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2012, 109 (40) :16202-16207
[9]   Zfp281 Functions as a Transcriptional Repressor for Pluripotency of Mouse Embryonic Stem Cells [J].
Fidalgo, Miguel ;
Shekar, P. Chandra ;
Ang, Yen-Sin ;
Fujiwara, Yuko ;
Orkin, Stuart H. ;
Wang, Jianlong .
STEM CELLS, 2011, 29 (11) :1705-1716
[10]   Heterogeneity of Embryonic and Adult Stem Cells [J].
Graf, Thomas ;
Stadtfeld, Matthias .
CELL STEM CELL, 2008, 3 (05) :480-483