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dc.contributor.authorSpielmann, Malte
dc.contributor.authorSantos-Simarro, Fernando
dc.contributor.authorGilbert-Dussardier, Brigitte
dc.contributor.authorWittler, Lars
dc.contributor.authorBorschiwer, Marina
dc.contributor.authorHaas, Stefan A.
dc.contributor.authorOsterwalder, Marco
dc.contributor.authorFranke, Martin
dc.contributor.authorTimmermann, Bernd
dc.contributor.authorHecht, Jochen
dc.contributor.authorVisel, Axel
dc.contributor.authorMundlos, Stefan
dc.contributor.authorKayserili, Hulya
dc.contributor.authorLupianez, Dario G.
dc.contributor.authorKraft, Katerina
dc.contributor.authorHeinrich, Verena
dc.contributor.authorKrawitz, Peter
dc.contributor.authorBrancati, Francesco
dc.contributor.authorKlopocki, Eva
dc.contributor.authorHom, Denise
dc.contributor.authorOpitz, John M.
dc.contributor.authorLaxova, Renata
dc.date.accessioned2021-03-05T12:37:29Z
dc.date.available2021-03-05T12:37:29Z
dc.date.issued2015
dc.identifier.citationLupianez D. G. , Kraft K., Heinrich V., Krawitz P., Brancati F., Klopocki E., Hom D., Kayserili H., Opitz J. M. , Laxova R., et al., "Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions", CELL, cilt.161, ss.1012-1025, 2015
dc.identifier.issn0092-8674
dc.identifier.othervv_1032021
dc.identifier.otherav_ae0fb57b-8fb7-4607-b1ec-2bd707f7d761
dc.identifier.urihttp://hdl.handle.net/20.500.12627/116126
dc.identifier.urihttps://doi.org/10.1016/j.cell.2015.04.004
dc.description.abstractMammalian 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.
dc.language.isoeng
dc.subjectBİYOKİMYA VE MOLEKÜLER BİYOLOJİ
dc.subjectYaşam Bilimleri (LIFE)
dc.subjectHÜCRE BİYOLOJİSİ
dc.subjectTıp
dc.subjectSağlık Bilimleri
dc.subjectTemel Tıp Bilimleri
dc.subjectHistoloji-Embriyoloji
dc.subjectYaşam Bilimleri
dc.subjectMoleküler Biyoloji ve Genetik
dc.subjectSitogenetik
dc.subjectTemel Bilimler
dc.subjectMoleküler Biyoloji ve Genetik
dc.titleDisruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions
dc.typeMakale
dc.relation.journalCELL
dc.contributor.departmentİstanbul Üniversitesi , ,
dc.identifier.volume161
dc.identifier.issue5
dc.identifier.startpage1012
dc.identifier.endpage1025
dc.contributor.firstauthorID222097


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