| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2019 |
| Předmět: |
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| Zdroj: |
Stem Cell Reports, Vol 12, Iss 6, Pp 1342-1353 (2019) |
| Druh dokumentu: |
article |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2019.04.012 |
| Popis: |
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 |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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