Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci
Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-06-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671119301341 |
| _version_ | 1828525372678864896 |
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| author | Erin N. Smith Agnieszka D'Antonio-Chronowska William W. Greenwald Victor Borja Lana R. Aguiar Robert Pogue Hiroko Matsui Paola Benaglio Shyamanga Borooah Matteo D'Antonio Radha Ayyagari Kelly A. Frazer |
| author_facet | Erin N. Smith Agnieszka D'Antonio-Chronowska William W. Greenwald Victor Borja Lana R. Aguiar Robert Pogue Hiroko Matsui Paola Benaglio Shyamanga Borooah Matteo D'Antonio Radha Ayyagari Kelly A. Frazer |
| author_sort | Erin N. Smith |
| collection | DOAJ |
| description | Summary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD. : Smith, D'Antonio-Chronowska, and colleagues integrate newly generated epigenetic and transcriptomic data from iPSC-derived retinal pigment epithelium with data from adult samples to prioritize potential causal variants associated with age-related macular degeneration. They prioritize rs943080 at the VEGFA locus and show that the risk allele may reduce VEGFA gene expression by altering activity of a distal regulatory region. Keywords: induced pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, VEGFA, chromatin accessibility, fine mapping, regulatory variants, genome-wide association, iPSC-RPE |
| first_indexed | 2024-12-11T21:04:35Z |
| format | Article |
| id | doaj.art-9c34a3ce8fe74c1c8d965a279b15f664 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-11T21:04:35Z |
| publishDate | 2019-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-9c34a3ce8fe74c1c8d965a279b15f6642022-12-22T00:50:53ZengElsevierStem Cell Reports2213-67112019-06-0112613421353Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk LociErin N. Smith0Agnieszka D'Antonio-Chronowska1William W. Greenwald2Victor Borja3Lana R. Aguiar4Robert Pogue5Hiroko Matsui6Paola Benaglio7Shyamanga Borooah8Matteo D'Antonio9Radha Ayyagari10Kelly A. Frazer11Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USAInstitute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USABioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA 92093, USAInstitute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USAInstitute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, BrazilPrograma de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, DF, BrazilInstitute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USADepartment of Pediatrics, University of California San Diego, La Jolla, CA 92093, USACentre for Clinical Brain Sciences, School of Clinical Sciences, The University of Edinburgh, Edinburgh, UK; Shiley Eye Institute, University of California San Diego, La Jolla, CA 92093, USAInstitute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USAShiley Eye Institute, University of California San Diego, La Jolla, CA 92093, USADepartment of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA; Institute for Genomic Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Cellular and Molecular Medicine East, 9500 Gilman Drive #0761, La Jolla, CA 92093-0761, USA; Corresponding authorSummary: We evaluate whether human induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) cells can be used to prioritize and functionally characterize causal variants at age-related macular degeneration (AMD) risk loci. We generated iPSC-RPE from six subjects and show that they have morphological and molecular characteristics similar to those of native RPE. We generated RNA-seq, ATAC-seq, and H3K27ac ChIP-seq data and observed high similarity in gene expression and enriched transcription factor motif profiles between iPSC-RPE and human fetal RPE. We performed fine mapping of AMD risk loci by integrating molecular data from the iPSC-RPE, adult retina, and adult RPE, which identified rs943080 as the probable causal variant at VEGFA. We show that rs943080 is associated with altered chromatin accessibility of a distal ATAC-seq peak, decreased overall gene expression of VEGFA, and allele-specific expression of a non-coding transcript. Our study thus provides a potential mechanism underlying the association of the VEGFA locus with AMD. : Smith, D'Antonio-Chronowska, and colleagues integrate newly generated epigenetic and transcriptomic data from iPSC-derived retinal pigment epithelium with data from adult samples to prioritize potential causal variants associated with age-related macular degeneration. They prioritize rs943080 at the VEGFA locus and show that the risk allele may reduce VEGFA gene expression by altering activity of a distal regulatory region. Keywords: induced pluripotent stem cells, retinal pigment epithelium, age-related macular degeneration, VEGFA, chromatin accessibility, fine mapping, regulatory variants, genome-wide association, iPSC-RPEhttp://www.sciencedirect.com/science/article/pii/S2213671119301341 |
| spellingShingle | Erin N. Smith Agnieszka D'Antonio-Chronowska William W. Greenwald Victor Borja Lana R. Aguiar Robert Pogue Hiroko Matsui Paola Benaglio Shyamanga Borooah Matteo D'Antonio Radha Ayyagari Kelly A. Frazer Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci Stem Cell Reports |
| title | Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci |
| title_full | Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci |
| title_fullStr | Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci |
| title_full_unstemmed | Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci |
| title_short | Human iPSC-Derived Retinal Pigment Epithelium: A Model System for Prioritizing and Functionally Characterizing Causal Variants at AMD Risk Loci |
| title_sort | human ipsc derived retinal pigment epithelium a model system for prioritizing and functionally characterizing causal variants at amd risk loci |
| url | http://www.sciencedirect.com/science/article/pii/S2213671119301341 |
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