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  Dynamic 3D chromatin architecture determines enhancer specificity and morphogenetic identity in limb development

Kragesteen, B. K., Spielmann, M., Paliou, C., Heinrich, V., Schöpflin, R., Esposito, A., et al. (2018). Dynamic 3D chromatin architecture determines enhancer specificity and morphogenetic identity in limb development. Nature Genetics, 50(10), 1463-1473. doi:10.1038/s41588-018-0221-x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-7E55-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-7E56-1
Genre: Journal Article

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Kragesteen , Bjørt K. 1, Author
Spielmann, Malte1, Author              
Paliou, Christina1, Author
Heinrich, Verena2, Author              
Schöpflin, Robert1, 3, Author              
Esposito, Andrea , Author
Annunziatella, Carlo , Author
Bianco , Simona , Author
Chiariello, Andrea M. , Author
Jerković , Ivana1, Author
Harabula, Izabela 1, Author
Guckelberger, Philine 1, Author
Pechstein, Michael , Author
Wittler, Lars4, Author              
Chan, Wing-Lee , Author
Franke, Martin1, Author
Lupiáñez , Darío G. 1, Author
Kraft, Katerina1, Author              
Timmermann, Bernd5, Author              
Vingron, Martin2, Author              
Visel, Axel, AuthorNicodemi, Mario , AuthorMundlos, Stefan1, Author              Andrey, Guillaume 1, Author more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
3Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
4Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
5Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 Abstract: The regulatory specificity of enhancers and their interaction with gene promoters is thought to be controlled by their sequence and the binding of transcription factors. By studying Pitx1, a regulator of hindlimb development, we show that dynamic changes in chromatin conformation can restrict the activity of enhancers. Inconsistent with its hindlimb-restricted expression, Pitx1 is controlled by an enhancer (Pen) that shows activity in forelimbs and hindlimbs. By Capture Hi-C and three-dimensional modeling of the locus, we demonstrate that forelimbs and hindlimbs have fundamentally different chromatin configurations, whereby Pen and Pitx1 interact in hindlimbs and are physically separated in forelimbs. Structural variants can convert the inactive into the active conformation, thereby inducing Pitx1 misexpression in forelimbs, causing partial arm-to-leg transformation in mice and humans. Thus, tissue-specific three-dimensional chromatin conformation can contribute to enhancer activity and specificity in vivo and its disturbance can result in gene misexpression and disease.

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Language(s): eng - English
 Dates: 2018-09-272018-10
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41588-018-0221-x
 Degree: -

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Title: Nature Genetics
  Other : Nature Genet.
Source Genre: Journal
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Publ. Info: New York, NY : Nature America, Inc.
Pages: - Volume / Issue: 50 (10) Sequence Number: - Start / End Page: 1463 - 1473 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609