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  Genomic dissection of enhancers uncovers principles of combinatorial regulation and dynamic wiring of enhancer-promoter contacts

Thormann, V., Rothkegel, M. C., Schöpflin, R., Glaser, L. V., Djuric, P., Li, N., et al. (2018). Genomic dissection of enhancers uncovers principles of combinatorial regulation and dynamic wiring of enhancer-promoter contacts. Nucleic Acids Research (London), 46(6), 2868-2882. doi:10.1093/nar/gky051.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5189-7 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-518A-6
Genre: Journal Article

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 Creators:
Thormann, Verena1, Author              
Rothkegel, Maika C.1, Author              
Schöpflin, Robert2, Author              
Glaser, Laura V.1, Author              
Djuric, Peter, Author
Li, Na3, Author              
Chung, Ho-Ryun3, Author              
Schwahn, Kevin, Author
Vingron, Martin4, Author              
Meijsing, Sebastiaan1, Author              
Affiliations:
1Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479641              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
3Epigenomics (Ho-Ryun Chung), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479658              
4Gene 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: Genomic binding of transcription factors, like the glucocorticoid receptor (GR), is linked to the regulation of genes. However, as we show here, GR binding is a poor predictor of GR-dependent gene regulation even when taking the 3D organization of the genome into account. To connect GR binding sites to the regulation of genes in the endogenous genomic context, we turned to genome editing. By deleting GR binding sites, individually or in combination, we uncovered how cooperative interactions between binding sites contribute to the regulation of genes. Specifically, for the GR target gene GILZ, we show that the simultaneous presence of a cluster of GR binding sites is required for the activity of an individual enhancer and that the GR-dependent regulation of GILZ depends on multiple GR-bound enhancers. Further, by deleting GR binding sites that are shared between different cell types, we show how cell type-specific genome organization and enhancer-blocking can result in cell type-specific wiring of promoter-enhancer contacts. This rewiring allows an individual GR binding site shared between different cell types to direct the expression of distinct transcripts and thereby contributes to the cell type-specific consequences of glucocorticoid signaling.

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Language(s): eng - English
 Dates: 2018-01-192018-01-272018-04-06
 Publication Status: Published in print
 Pages: -
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 Rev. Method: -
 Identifiers: DOI: 10.1093/nar/gky051
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Title: Nucleic Acids Research (London)
  Alternative Title : Nucleic Acids Res
Source Genre: Journal
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Publ. Info: Oxford : Oxford University Press
Pages: 15 Volume / Issue: 46 (6) Sequence Number: - Start / End Page: 2868 - 2882 Identifier: n.a.: https://pure.mpg.de/cone/journals/resource/110992357379342