Combinatorial Binding in Human and Mouse Embryonic Stem Cells Identifies Conserved Enhancers Active in Early Embryonic Development

Göke, Jonathan; Jung, Marc; Behrens, Sarah; Chavez, Lukas; O'Keeffe, Sean; Timmermann, Bernd; Lehrach, Hans; Adjaye, James; Vingron, Martin
December 2011
PLoS Computational Biology;Dec2011, Vol. 7 Issue 12, Special section p1
Academic Journal
Transcription factors are proteins that regulate gene expression by binding to cis-regulatory sequences such as promoters and enhancers. In embryonic stem (ES) cells, binding of the transcription factors OCT4, SOX2 and NANOG is essential to maintain the capacity of the cells to differentiate into any cell type of the developing embryo. It is known that transcription factors interact to regulate gene expression. In this study we show that combinatorial binding is strongly associated with colocalization of the transcriptional co-activator Mediator, H3K27ac and increased expression of nearby genes in embryonic stem cells. We observe that the same loci bound by Oct4, Nanog and Sox2 in ES cells frequently drive expression in early embryonic development. Comparison of mouse and human ES cells shows that less than 5% of individual binding events for OCT4, SOX2 and NANOG are shared between species. In contrast, about 15% of combinatorial binding events and even between 53% and 63% of combinatorial binding events at enhancers active in early development are conserved. Our analysis suggests that the combination of OCT4, SOX2 and NANOG binding is critical for transcription in ES cells and likely plays an important role for embryogenesis by binding at conserved early developmental enhancers. Our data suggests that the fast evolutionary rewiring of regulatory networks mainly affects individual binding events, whereas "gene regulatory hotspots" which are bound by multiple factors and active in multiple tissues throughout early development are under stronger evolutionary constraints.


Related Articles

  • HeOtx expression in an indirectly developing polychaete correlates with gastrulation by invagination. Arenas-Mena, Cesar; SukYing Wong, Kimberly // Development Genes & Evolution;May2007, Vol. 217 Issue 5, p373 

    The expression of an Otx homolog in the indirectly developing polychaete Hydroides elegans was characterized during embryo, trochophore, and feeding-larva stages. In the animal hemisphere, HeOtx is first expressed in 1q12 blastomeres and their immediate descendants. Such discrete embryonic...

  • LifeMap Discoveryâ„¢: The Embryonic Development, Stem Cells, and Regenerative Medicine Research Portal. Edgar, Ron; Mazor, Yaron; Rinon, Ariel; Blumenthal, Jacob; Golan, Yaron; Buzhor, Ella; Livnat, Idit; Ben-Ari, Shani; Lieder, Iris; Shitrit, Alina; Gilboa, Yaron; Ben-Yehudah, Ahmi; Edri, Osnat; Shraga, Netta; Bogoch, Yoel; Leshansky, Lucy; Aharoni, Shlomi; West, Michael D.; Warshawsky, David; Shtrichman, Ronit // PLoS ONE;Jul2013, Vol. 8 Issue 7, p1 

    LifeMap Discoveryâ„¢ provides investigators with an integrated database of embryonic development, stem cell biology and regenerative medicine. The hand-curated reconstruction of cell ontology with stem cell biology; including molecular, cellular, anatomical and disease-related information,...

  • Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. MacArthur, Ben D.; Sevilla, Ana; Lenz, Michel; Müller, Franz-Josef; Schuldt, Berhard M.; Schuppert, Andreas A.; Ridden, Sonya J.; Stumpf, Patrick S.; Fidalgo, Miguel; Ma'ayan, Avi; Wang, Jianlong; Lemischka, Ihor R. // Nature Cell Biology;Nov2012, Vol. 14 Issue 11, p1139 

    A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate...

  • Regulation of Pax6 by CTCF during Induction of Mouse ES Cell Differentiation. Jie Gao; Jie Wang; Yumei Wang; Wei Dai; Luo Lu // PLoS ONE;2011, Vol. 6 Issue 6, p1 

    Pax6 plays an important role in embryonic cell (ES) differentiation during embryonic development. Expression of Pax6 undergoes from a low level to high levels following ES cell differentiation to neural stem cells, and then fades away in most of the differentiated cell types. There is a limited...

  • 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 // PLoS Biology;Jul2009, Vol. 7 Issue 7, p1 

    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...

  • Stem cells: Holding on to the memories. Baumann, Kim // Nature Reviews Molecular Cell Biology;Sep2010, Vol. 11 Issue 9, p601 

    The article discusses research being done on pluripotent embryonic stem cells (ES). It references the study "Epigenetic memory in induced pluripotent stem cells" by K. Kim and colleagues in the July 19, 2010 issue of "Nature." It states the differentiation potential of nuclear transfer embryonic...

  • Oct4 and the small molecule inhibitor, SC1, regulates Tet2 expression in mouse embryonic stem cells. Wu, Yongyan; Guo, Zekun; Liu, Ye; Tang, Bo; Wang, Yi; Yang, Liping; Du, Juan; Zhang, Yong // Molecular Biology Reports;Apr2013, Vol. 40 Issue 4, p2897 

    The ten eleven translocation (Tet) family of proteins includes three members (Tet1-3), all of which have the capacity to convert 5-methylcytosine to 5-hydroxymethylcytosine in a 2-oxoglutarate- and Fe(II)-dependent manner. Tet1 and Tet2 are highly expressed in undifferentiated embryonic stem...

  • 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...

  • Probing the role of stochasticity in a model of the embryonic stem cell--heterogeneous gene expression and reprogramming efficiency. Chickarmane, Vijay; Olariu, Victor; Peterson, Carsten // BMC Systems Biology;2012, Vol. 6 Issue 1, p98 

    Background: Embryonic stem cells (ESC) have the capacity to self-renew and remain pluripotent, while continuously providing a source of a variety of differentiated cell types. Understanding what governs these properties at the molecular level is crucial for stem cell biology and its application...


Read the Article


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

Try another library?
Sign out of this library

Other Topics