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  Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture

Despang, A., Schöpflin, R., Franke, M., Ali, S., Jerković, I., Paliou, C., et al. (2019). Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nature Genetics, 51(8), 1263-1271. doi:10.1038/s41588-019-0466-z.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-98FD-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-98FE-3
Genre: Journal Article

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 Creators:
Despang, Alexandra1, Author              
Schöpflin, Robert1, Author              
Franke, Martin1, Author              
Ali, Salaheddine1, Author              
Jerković, Ivana, Author
Paliou, Christina1, Author              
Chan, Wing-Lee, Author
Timmermann, Bernd2, Author              
Wittler, Lars3, Author              
Vingron, Martin4, Author              
Mundlos, Stefan1, Author              
Ibrahim, Daniel M.1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
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: The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9-Kcnj2 locus. We show that the removal of all major CTCF sites at the boundary and within the TAD resulted in a fusion of neighboring TADs, without major effects on gene expression. Gene misexpression and disease phenotypes, however, were achieved by redirecting regulatory activity through inversions and/or the repositioning of boundaries. Thus, TAD structures provide robustness and precision but are not essential for developmental gene regulation. Aberrant disease-related gene activation is not induced by a mere loss of insulation but requires CTCF-dependent redirection of enhancer-promoter contacts.

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Language(s): eng - English
 Dates: 2019-07-292019-08
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/s41588-019-0466-z
PMID: 31358994
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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: 9 Volume / Issue: 51 (8) Sequence Number: - Start / End Page: 1263 - 1271 Identifier: ISSN: 1061-4036
CoNE: https://pure.mpg.de/cone/journals/resource/954925598609