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  Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations

Kraft, K., Magg, A., Heinrich, V., Riemenschneider, C., Schöpflin, R., Markowski, J., et al. (2019). Serial genomic inversions induce tissue-specific architectural stripes, gene misexpression and congenital malformations. Nature Cell Biology, 21(3), 305-310. doi:10.1038/s41556-019-0273-x.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-1BB5-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-1BB6-2
Genre: Journal Article

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 Creators:
Kraft, Katerina1, Author              
Magg, Andreas1, Author              
Heinrich, Verena2, Author              
Riemenschneider, Christina3, Author              
Schöpflin, Robert1, Author              
Markowski, Julia, Author
Ibrahim, Daniel1, Author              
Acuna-Hidalgo, Rocío , Author
Despang, Alexandra1, Author              
Andrey, Guillaume, Author
Wittler, Lars4, Author              
Timmermann, Bernd5, Author              
Vingron, Martin2, Author              
Mundlos, Stefan1, Author              
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 Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
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: Balanced chromosomal rearrangements such as inversions and translocations can cause congenital disease or cancer by inappropriately rewiring promoter-enhancer contacts1,2. To study the potentially pathogenic consequences of balanced chromosomal rearrangements, we generated a series of genomic inversions by placing an active limb enhancer cluster from the Epha4 regulatory domain at different positions within a neighbouring gene-dense region and investigated their effects on gene regulation in vivo in mice. Expression studies and high-throughput chromosome conformation capture from embryonic limb buds showed that the enhancer cluster activated several genes downstream that are located within asymmetric regions of contact, the so-called architectural stripes3. The ectopic activation of genes led to a limb phenotype that could be rescued by deleting the CCCTC-binding factor (CTCF) anchor of the stripe. Architectural stripes appear to be driven by enhancer activity, because they do not form in mouse embryonic stem cells. Furthermore, we show that architectural stripes are a frequent feature of developmental three-dimensional genome architecture often associated with active enhancers. Therefore, balanced chromosomal rearrangements can induce ectopic gene expression and the formation of asymmetric chromatin contact patterns that are dependent on CTCF anchors and enhancer activity.

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Language(s): eng - English
 Dates: 2019-01-022019-02-112019-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.1038/s41556-019-0273-x
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Title: Nature Cell Biology
  Other : 'Nat. Cell Biol.'
Source Genre: Journal
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Publ. Info: London : Macmillan Magazines Ltd.
Pages: 6 Volume / Issue: 21 (3) Sequence Number: - Start / End Page: 305 - 310 Identifier: ISSN: 1465-7392
CoNE: https://pure.mpg.de/cone/journals/resource/954925625310