OCT4/SOX2-independent Nanog autorepression modulates heterogeneous Nanog gene expression in mouse ES cells
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 exh...
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Published in | The EMBO journal Vol. 31; no. 24; pp. 4547 - 4562 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Chichester, UK
John Wiley & Sons, Ltd
12.12.2012
Nature Publishing Group UK Blackwell Publishing Ltd EMBO Press Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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 discovery of
Nanog
autorepression offers a new perspective on the transcriptional networks that govern
Nanog's
heterogeneous expression in ES cells. |
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Bibliography: | Supplementary InformationReview Process File ArticleID:EMBJ2012321 istex:73C6B2A2017FCC4F17C9EA6215E2F64582C0B918 ark:/67375/WNG-KFLVD2B3-P ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 PMCID: PMC3545296 Present address: Wellcome Trust Sanger Institute, Hinxton CB10 1HH, England Present address: MRC Human Genetics Unit, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, Scotland |
ISSN: | 0261-4189 1460-2075 |
DOI: | 10.1038/emboj.2012.321 |