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Multi-omics approach dissects cis-regulatory mechanisms underlying North Carolina macular dystrophy, a retinal enhanceropathy
S. Van de Sompele, KW. Small, MB. Cicekdal, VL. Soriano, E. D'haene, FS. Shaya, S. Agemy, T. Van der Snickt, AD. Rey, T. Rosseel, M. Van Heetvelde, S. Vergult, I. Balikova, AA. Bergen, CJF. Boon, J. De Zaeytijd, CF. Inglehearn, B. Kousal, BP....
Language English Country United States
Document type Journal Article
NLK
Cell Press Free Archives
from 1997-01-01 to 6 months ago
Free Medical Journals
from 1949 to 6 months ago
PubMed Central
from 1949 to 6 months ago
Europe PubMed Central
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Open Access Digital Library
from 2005-01-01
- MeSH
- Corneal Dystrophies, Hereditary * MeSH
- Adult MeSH
- Humans MeSH
- Tomography, Optical Coherence * MeSH
- Retina metabolism MeSH
- Pedigree MeSH
- Xenopus laevis genetics MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
Bartiméus Diagnostic Center for Complex Visual Disorders Zeist The Netherlands
Center for Medical Genetics Antwerp University Hospital Antwerp Belgium
Center for Medical Genetics Ghent University Hospital Ghent Belgium
Department of Biomedical Molecular Biology Ghent University Ghent Belgium
Department of Biomolecular Medicine Ghent University Ghent Belgium
Department of Genetics and Genome Biology University of Leicester Leicester UK
Department of Head and Skin Ghent University Ghent Belgium
Department of Human Genetics Amsterdam UMC Academic Medical Center 1105 AZ Amsterdam The Netherlands
Department of Ophthalmology Ghent University Hospital Ghent Belgium
Department of Ophthalmology Leiden University Medical Center Leiden The Netherlands
Department of Ophthalmology SUNY Downstate Medical Center University Brooklyn New York USA
Department of Ophthalmology University Hospitals Leuven Leuven Belgium
Department of Ophthalmology University of Basel Basel Switzerland
Division of Molecular Medicine Leeds Institute of Medical Research University of Leeds Leeds UK
Institute of Molecular and Clinical Ophthalmology Basel Basel Switzerland
Macula and Retina Institute Los Angeles and Glendale California USA
University of Lausanne Jules Gonin Eye Hospital Lausanne Switzerland
References provided by Crossref.org
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- $a North Carolina macular dystrophy (NCMD) is a rare autosomal-dominant disease affecting macular development. The disease is caused by non-coding single-nucleotide variants (SNVs) in two hotspot regions near PRDM13 and by duplications in two distinct chromosomal loci, overlapping DNase I hypersensitive sites near either PRDM13 or IRX1. To unravel the mechanisms by which these variants cause disease, we first established a genome-wide multi-omics retinal database, RegRet. Integration of UMI-4C profiles we generated on adult human retina then allowed fine-mapping of the interactions of the PRDM13 and IRX1 promoters and the identification of eighteen candidate cis-regulatory elements (cCREs), the activity of which was investigated by luciferase and Xenopus enhancer assays. Next, luciferase assays showed that the non-coding SNVs located in the two hotspot regions of PRDM13 affect cCRE activity, including two NCMD-associated non-coding SNVs that we identified herein. Interestingly, the cCRE containing one of these SNVs was shown to interact with the PRDM13 promoter, demonstrated in vivo activity in Xenopus, and is active at the developmental stage when progenitor cells of the central retina exit mitosis, suggesting that this region is a PRDM13 enhancer. Finally, mining of single-cell transcriptional data of embryonic and adult retina revealed the highest expression of PRDM13 and IRX1 when amacrine cells start to synapse with retinal ganglion cells, supporting the hypothesis that altered PRDM13 or IRX1 expression impairs interactions between these cells during retinogenesis. Overall, this study provides insight into the cis-regulatory mechanisms of NCMD and supports that this condition is a retinal enhanceropathy.
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