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dc.contributor.authorPorter, Louise
dc.contributor.authorGalli, Giorgio
dc.contributor.authorWilliamson, Sally
dc.contributor.authorSelley, Julian
dc.contributor.authorKnight, David
dc.contributor.authorElcioğlu, Nursel
dc.contributor.authorAydın, Ali
dc.contributor.authorElcioğlu, Mustafa
dc.contributor.authorVenselaar, Hanka
dc.contributor.authorLund, Anders
dc.contributor.authorBonshek, Richard
dc.contributor.authorBlack, Graeme
dc.contributor.authorManson, Forbes
dc.date.accessioned2020-06-25T12:15:00Z
dc.date.available2020-06-25T12:15:00Z
dc.date.issued2015en_US
dc.identifier.citationPorter, L., Galli, G., Williamson, S., Selley, J., Knight, D. Elcioğlu, N. ... Manson, F. (2015). A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome. Human Molecular Genetics, 24(23), 6565-6579. https://dx.doi.org/10.1093/hmg/ddv345en_US
dc.identifier.issn0964-6906
dc.identifier.issn1460-2083
dc.identifier.urihttps://dx.doi.org/10.1093/hmg/ddv345
dc.identifier.urihttps://hdl.handle.net/20.500.12511/5304
dc.description.abstractType 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 (PRDM5) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5. exons 9-14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and. exons 9-14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures (COL13A1, COL15A1, NTN1, CDH5) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9-14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Delta exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.en_US
dc.description.sponsorshipNational Institute for Health Research Action Medical Research National Institute for Health Research American-Italian Cancer Foundation postdoctoral research fellowship National Institute for Health Researchen_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectRepressiveen_US
dc.subjectComplexesen_US
dc.subjectCornea Syndromeen_US
dc.titleA role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndromeen_US
dc.typearticleen_US
dc.relation.journalHuman Molecular Geneticsen_US
dc.departmentİstanbul Medipol Üniversitesi, Tıp Fakültesi, Cerrahi Tıp Bilimleri Bölümü, Göz Hastalıkları Ana Bilim Dalıen_US
dc.authorid0000-0002-0972-3833en_US
dc.identifier.volume24en_US
dc.identifier.issue23en_US
dc.identifier.startpage6565en_US
dc.identifier.endpage6579en_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.identifier.doi10.1093/hmg/ddv345en_US


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