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  Formation of novel chromatin domains determines pathogenicity of genomic duplications

Franke, M., Ibrahim, D., Andrey, G., Schwarzer, W., Heinrich, V., Schöpflin, R., et al. (2016). Formation of novel chromatin domains determines pathogenicity of genomic duplications. Nature, 538(7624), 265-269. doi:10.1038/nature19800.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-010A-3 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002C-010B-1
Genre: Journal Article

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 Creators:
Franke, Martin, Author
Ibrahim, Daniel1, Author              
Andrey, Guillaume , Author
Schwarzer, Wibke1, Author              
Heinrich, Verena, Author
Schöpflin, Robert2, Author              
Kraft, Katerina1, Author              
Kempfer, Rieke, Author
Jerković, Ivana , Author
Chan, Wing-Lee, Author
Spielmann, Malte1, Author              
Timmermann, Bernd3, Author              
Wittler, Lars4, Author              
Kurth, Ingo, Author
Cambiaso, Paola , Author
Zuffardi, Orsetta , Author
Houge, Gunnar, Author
Lambie, Lindsay , Author
Brancati, Francesco , Author
Pombo, Ana, Author
Vingron, Martin5, Author              Spitz, Francois , AuthorMundlos, Stefan1, Author               more..
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
3Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
4Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
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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Free keywords: Gene regulation Gene duplication Chromatin structure Disease model Disease genetics
 Abstract: Chromosome conformation capture methods have identified subchromosomal structures of higher-order chromatin interactions called topologically associated domains (TADs) that are separated from each other by boundary regions1, 2. By subdividing the genome into discrete regulatory units, TADs restrict the contacts that enhancers establish with their target genes3, 4, 5. However, the mechanisms that underlie partitioning of the genome into TADs remain poorly understood. Here we show by chromosome conformation capture (capture Hi-C and 4C-seq methods) that genomic duplications in patient cells and genetically modified mice can result in the formation of new chromatin domains (neo-TADs) and that this process determines their molecular pathology. Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans6, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure. In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome. As a consequence of this insulation, inter-TAD duplications had no phenotypic effect. However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype. Our findings provide evidence that TADs are genomic regulatory units with a high degree of internal stability that can be sculptured by structural genomic variations. This process is important for the interpretation of copy number variations, as these variations are routinely detected in diagnostic tests for genetic disease and cancer. This finding also has relevance in an evolutionary setting because copy-number differences are thought to have a crucial role in the evolution of genome complexity.

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Language(s): eng - English
 Dates: 2016-08-232016-10-052016-10-13
 Publication Status: Published in print
 Pages: 5
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/nature19800
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 538 (7624) Sequence Number: - Start / End Page: 265 - 269 Identifier: ISSN: 0028-0836
CoNE: /journals/resource/954925427238