Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells

Kalmar, Tibor; Lim, Chea; Hayward, Penelope; Muñoz-Descalzo, Silvia; Nichols, Jennifer; Garcia-Ojalvo, Jordi; Arias, Alfonso Martinez
July 2009
PLoS Biology;Jul2009, Vol. 7 Issue 7, p1
Academic Journal
There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5%-20% of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals.


Related Articles

  • A core Klf circuitry regulates self-renewal of embryonic stem cells. Jianming Jiang; Yun-Shen Chan; Yuin-Han Loh; Jun Cai; Guo-Qing Tong; Ching-Aeng Lim; Robson, Paul; Sheng Zhong; Huck-Hui Ng // Nature Cell Biology;Mar2008, Vol. 10 Issue 3, p353 

    Embryonic stem (ES) cells are unique in their ability to self-renew indefinitely and maintain pluripotency. These properties require transcription factors that specify the gene expression programme of ES cells. It has been possible to reverse the highly differentiated state of somatic cells back...

  • Network plasticity of pluripotency transcription factors in embryonic stem cells. Hastreiter, Simon; Hoppe, Philipp S.; Loeffler, Dirk; Kokkaliaris, Konstantinos D.; Endele, Max; Schauberger, Bernhard; Hilsenbeck, Oliver; Skylaki, Stavroula; Hasenauer, Jan; Theis, Fabian J.; Schroeder, Timm; Filipczyk, Adam; Marr, Carsten; Feigelman, Justin; Schwarzfischer, Michael; Anastassiadis, Konstantinos // Nature Cell Biology;Oct2015, Vol. 17 Issue 10, p1235 

    Transcription factor (TF) networks are thought to regulate embryonic stem cell (ESC) pluripotency. However, TF expression dynamics and regulatory mechanisms are poorly understood. We use reporter mouse ESC lines allowing non-invasive quantification of Nanog or Oct4 protein levels and continuous...

  • Directed differentiation of human embryonic stem cells toward chondrocytes. Oldershaw, Rachel A.; Baxter, Melissa A.; Lowe, Emma T.; Bates, Nicola; Grady, Lisa M.; Soncin, Francesca; Brison, Daniel R.; Hardingham, Timothy E.; Kimber, Susan J. // Nature Biotechnology;Nov2010, Vol. 28 Issue 11, p1187 

    We report a chemically defined, efficient, scalable and reproducible protocol for differentiation of human embryonic stem cells (hESCs) toward chondrocytes. HESCs are directed through intermediate developmental stages using substrates of known matrix proteins and chemically defined media...

  • Co-regulation in embryonic stem cells via context-dependent binding of transcription factors. Lee, Yuju; Zhou, Qing // Bioinformatics;Sep2013, Vol. 29 Issue 17, p2162 

    Motivation: With the accumulation of genome-wide binding data for many transcription factors (TFs) in the same cell type or cellular condition, it is of great current interest to systematically infer the complex regulatory logic among multiple TFs. In particular, ChIP-Seq data have been...

  • The RNA-Binding Protein Unr Prevents Mouse Embryonic Stem Cells Differentiation Toward the Primitive Endoderm Lineage. Elatmani, Habiba; Dormoy-Raclet, Virginie; Dubus, Pierre; Dautry, François; Chazaud, Claire; Jacquemin-Sablon, Hélène // Stem Cells (Wiley-Blackwell);Oct2011, Vol. 29 Issue 10, p1504 

    The maintenance of embryonic stem cells (ESCs) pluripotency depends on key transcription factors, chromatin remodeling proteins, and microRNAs. The roles of RNA-binding proteins are however poorly understood. We report that the cytoplasmic RNA-binding protein Unr prevents the differentiation of...

  • Triggering neural differentiation of ES cells by subtype switching of importin-α. Yasuhara, Noriko; Shibazaki, Noriko; Tanaka, Shinya; Nagai, Masahiro; Kamikawa, Yasunao; Oe, Souichi; Asally, Munehiro; Kamachi, Yusuke; Kondoh, Hisato; Yoneda, Yoshihiro // Nature Cell Biology;Jan2007, Vol. 9 Issue 1, p72 

    Nuclear proteins are selectively imported into the nucleus by transport factors such as importin-α and importin-β. Here, we show that the expression of importin-α subtypes is strictly regulated during neural differentiation of mouse embryonic stem (ES) cells, and that the switching of...

  • DNA Methylation Restricts Lineage-specific Functions of Transcription Factor Gata4 during Embryonic Stem Cell Differentiation. Oda, Masaaki; Kumaki, Yuichi; Shigeta, Masaki; Jakt, Lars Martin; Matsuoka, Chisa; Yamagiwa, Akiko; Niwa, Hitoshi; Okano, Masaki // PLoS Genetics;Jun2013, Vol. 9 Issue 6, p1 

    DNA methylation changes dynamically during development and is essential for embryogenesis in mammals. However, how DNA methylation affects developmental gene expression and cell differentiation remains elusive. During embryogenesis, many key transcription factors are used repeatedly, triggering...

  • A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal. Gagliardi, Alessia; Mullin, Nicholas P; Ying Tan, Zi; Colby, Douglas; Kousa, Anastasia I; Halbritter, Florian; Weiss, Jason T; Felker, Anastasia; Bezstarosti, Karel; Favaro, Rebecca; Demmers, Jeroen; Nicolis, Silvia K; Tomlinson, Simon R; Poot, Raymond A; Chambers, Ian // EMBO Journal;8/14/2013, Vol. 32 Issue 16, p2231 

    Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying...

  • The Oct4 protein: more than a magic stemness marker. Zeineddine, Dana; Aya Abou Hammoud; Mortada, Mohamad; Boeuf, Hélène // American Journal of Stem Cells;2014, Vol. 3 Issue 2, p74 

    The Oct4 protein, encoded by the Pou5f1 gene was the very first master gene, discovered 25 years ago, to be absolutely required for the stemness properties of murine and primate embryonic stem cells. This transcription factor, which has also been shown to be essential for somatic cell...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics