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

Item Type:Article
Title:Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions
Creators Name:Lupiáñez, D.G. and Kraft, K. and Heinrich, V. and Krawitz, P. and Brancati, F. and Klopocki, E. and Horn, D. and Kayserili, H. and Opitz, J.M. and Laxova, R. and Santos-Simarro, F. and Gilbert-Dussardier, B. and Wittler, L. and Borschiwer, M. and Haas, S.A. and Osterwalder, M. and Franke, M. and Timmermann, B. and Hecht, J. and Spielmann, M. and Visel, A. and Mundlos, S.
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.
Keywords:Animal Disease Models, Congenital Limb Deformities, EphA4 Receptor, Extremities, Gene Expression Regulation, Genetic Enhancer Elements, Genetic Promoter Regions, Untranslated RNA, Animals, Mice
Source:Cell
ISSN:0092-8674
Publisher:Cell Press (U.S.A.)
Volume:161
Number:5
Page Range:1012-1025
Date:21 May 2015
Official Publication:https://doi.org/10.1016/j.cell.2015.04.004
PubMed:View item in PubMed

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