Transcriptomics

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Disruptions of Topological Chromatin Domains Causes Pathogenic Rewiring of Gene-Enhancer Interactions [4C-Seq-mouse]


ABSTRACT: Mammalian genomes are organized into megabase-scale topologically associated domains (TADs) that have been proposed to represent large regulatory units. Here we demonstrate that disruption of TADs can cause rewiring of 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. 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. Circular Chromosome Conformation Capture (4C seq) at the Wnt6/Ihh/Epha4/Pax3 locus in developing distal limbs of mutants and WT animals at E11.5

ORGANISM(S): Mus musculus  

SUBMITTER: Stefan Mundlos  Darío G Lupiáñez    

PROVIDER: E-GEOD-66379 | ArrayExpress | 2015-05-08

SECONDARY ACCESSION(S): GSE66379SRP055673PRJNA276691

REPOSITORIES: GEO, ArrayExpress, ENA

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