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Cell. 2015 May 21;161(5):1012-1025. doi: 10.1016/j.cell.2015.04.004. Epub 2015 May 7.

Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions.

Author information

1
Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
2
Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
3
Medical Genetics Unit, Policlinico Tor Vergata University Hospital, 00133 Rome, Italy.
4
Institute of Human Genetics Biozentrum, Julius Maximilian University of Würzburg, 97070 Würzburg, Germany.
5
Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, 34093 Istanbul, Turkey.
6
Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, UT 84108, USA.
7
Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain; U753 Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28046 Madrid, Spain.
8
Service de Génétique, C.H.U. de Poitiers, 86021 Poitiers, France.
9
Department Developmental Genetics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
10
Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany.
11
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
12
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.
13
Max Planck Institute for Molecular Genetics, Sequencing Core Facility, 14195 Berlin, Germany.
14
Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
15
Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
16
Genomics Division, MS 84-171, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, USA; School of Natural Sciences, University of California, Merced, CA 95343, USA.
17
Max Planck Institute for Molecular Genetics, RG Development & Disease, 14195 Berlin, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: mundlos@molgen.mpg.de.

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.

PMID:
25959774
PMCID:
PMC4791538
DOI:
10.1016/j.cell.2015.04.004
[Indexed for MEDLINE]
Free PMC Article

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