Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa
| Autor: | Michel Michaelides, Michael E. Cheetham, Marco Aben, Alison J. Hardcastle, Hannie Kremer, Daniele Ottaviani, Stefan Mundlos, Graeme C.M. Black, Susan M Downes, Robert K. Koenekoop, Julio C. Corral-Serrano, Jordi Corominas, Gavin Arno, Andrew R. Webster, Claire E. L. Smith, Uirá Souto Melo, Carlo Rivolta, Suzanne E. de Bruijn, Chris F. Inglehearn, Raj Ramesar, L. Ingeborgh van den Born, Susanne Roosing, Christian Gilissen, Nikolas Pontikos, Musa M. Mhlanga, Jacquie Greenberg, F. Lucy Raymond, Frans P.M. Cremers, Alessia Fiorentino, Timo W. F. Mulders, Stephanie Fanucchi, Silvia Albert, Simon Mead, Lisa Roberts, Michalis Georgiou, George Rebello, Carel B. Hoyng |
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| Přispěvatelé: | Repositório da Universidade de Lisboa |
| Rok vydání: | 2020 |
| Předmět: |
Male
Gene Expression Enhancer RNAs Stem cells Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] Cohort Studies chemistry.chemical_compound Hi-C Induced pluripotent stem cell Child Genetics (clinical) Genes Dominant 0303 health sciences Genome 030305 genetics & heredity Chromosome Mapping Nuclear Proteins Cell Differentiation Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] Cellular Reprogramming Cell biology Organoids Enhancer Elements Genetic Ectopic expression Retinal Cone Photoreceptor Cells Photoreceptor precursors cells Female Dominant retinitis pigmentosa Topologically associated domains Retinitis Pigmentosa Human dominant retinitis pigmentosa ectopic expression GDPD photoreceptor precursors cells retinal organoids RP17 stem cells structural variants topologically associated domains whole-genome sequencing Adult Amino Acid Sequence Chromosomes Human Pair 17 Fibroblasts Genome Human Humans Induced Pluripotent Stem Cells Phosphoric Diester Hydrolases Polymorphism Genetic Primary Cell Culture Transcription Factors Whole Genome Sequencing Enhancer Elements Biology Chromosomes Article 03 medical and health sciences Genetic Retinitis pigmentosa Genetics medicine Dominant Polymorphism Enhancer Gene Transcription factor 030304 developmental biology Whole-genome sequencing Pair 17 Retinal organoids Retinal Cell Biology medicine.disease chemistry Genes Structural variants |
| Zdroj: | American Journal of Human Genetics, 107, 5, pp. 802-814 American Journal of Human Genetics, 107, 802-814 American Journal of Human Genetics Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| ISSN: | 0002-9297 |
| Popis: | © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases. |
| Databáze: | OpenAIRE |
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