English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

Lupiáñez, D. G., Kraft, K., Heinrich, V., Krawitz, P., Brancati, F., Klopocki, E., et al. (2015). Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions. Cell, 161(5), 1012-1025. doi:10.1016/j.cell.2015.04.004.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-A651-6 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60D2-A
Genre: Journal Article

Files

show Files
hide Files
:
Lupiánez.pdf (Publisher version), 4MB
Name:
Lupiánez.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© 2015 Elsevier B.V.
License:
-

Locators

show

Creators

show
hide
 Creators:
Lupiáñez, Darío G., Author
Kraft, Katerina, Author
Heinrich, Verena, Author
Krawitz, Peter, Author
Brancati, Francesco , Author
Klopocki, Eva, Author
Horn, Denise, Author
Kayserili, Hülya, Author
Opitz, John M., Author
Laxova, Renata , Author
Santos-Simarro, Fernando , Author
Gilbert-Dussardier, Brigitte , Author
Wittler, Lars1, Author              
Borschiwer, Marina2, Author              
Haas, Stefan A.3, Author              
Osterwalder, Marco, Author
Franke, Martin, Author
Timmermann, Bernd4, Author              
Hecht, Jochen2, Author              
Spielmann, Malte2, Author              
Visel, Axel, AuthorMundlos, Stefan2, Author               more..
Affiliations:
1Dept. of Developmental Genetics (Head: Bernhard G. Herrmann), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433548              
2Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
3Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
4Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

Content

show
hide
Free keywords: -
 Abstract: Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

Details

show
hide
Language(s): eng - English
 Dates: 2015-05-072015-05-21
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.cell.2015.04.004
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Cell
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Cambridge, Mass. : Cell Press
Pages: - Volume / Issue: 161 (5) Sequence Number: - Start / End Page: 1012 - 1025 Identifier: ISSN: 0092-8674
CoNE: /journals/resource/954925463183