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  Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development

Goke, J., Jung, M., Behrens, S., Chavez, L., O'Keeffe, S., Timmermann, B., et al. (2011). Combinatorial binding in human and mouse embryonic stem cells identifies conserved enhancers active in early embryonic development. PLoS Comput Biol, 7(12): e1002304.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0010-790C-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0029-2694-1
Genre: Journal Article

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 Creators:
Goke, J.1, Author              
Jung, M., Author
Behrens, S.1, Author              
Chavez, L.2, Author              
O'Keeffe, S., Author
Timmermann, B.3, Author              
Lehrach, H.2, Author              
Adjaye, J.4, Author              
Vingron, M.5, Author              
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
2Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433550              
3Sequencing, Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433559              
4Molecular Embryology and Aging (James Adjaye), Dept. of Vertebrate Genomics (Head: Hans Lehrach), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479654              
5Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              

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 Abstract: 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 co-localization 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.

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 Dates: 2011
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: eDoc: 584782
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Title: PLoS Comput Biol
Source Genre: Journal
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Pages: - Volume / Issue: 7 (12) Sequence Number: e1002304 Start / End Page: - Identifier: ISSN: 1553-7358 (Electronic) 1553-734X (Print)