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Dissecting genetic components associated with eye disease using integrative genomic analysis [RNA-seq]

ABSTRACT: GWAS studies have revealed thousands of variants strongly associated with AMD, yet connecting these variants to their cognate genes has not been explored. In this study we fine-mapped AMD risk loci and examined long-range cis chromatin interactions at essential genes of RPE function and disease-associated variants in iPSC-induced retinal pigmented epithelium (RPE) and primary RPE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE201680 | GEO | 2022/04/30

REPOSITORIES: GEO

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Dissecting genetic components associated with eye disease using integrative genomic analysis [ChIP-seq]

Project description:GWAS studies have revealed thousands of variants strongly associated with AMD, yet connecting these variants to their cognate genes has not been explored. In this study we fine-mapped AMD risk loci and examined long-range cis chromatin interactions at essential genes of RPE function and disease-associated variants in iPSC-induced retinal pigmented epithelium (RPE) and primary RPE.

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Dissecting genetic components associated with eye disease using integrative genomic analysis [Capture HiC]

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The LHX2-OTX2 regulatory module controls RPE differentiation and underlies a causal regulatory risk-SNP in age-related macular degeneration

Project description:Tissue-specific transcription factors control the transcriptome through an association with noncoding regulatory regions (cistromes). Identifying the combination of transcription factors that dictate specific cell fate, their specific cistromes and examining their involvement in complex human traits remain a major challenge. Here we focus on the retinal pigmented epithelium (RPE), an essential lineage for retinal development and function and the primary tissue affected in age-related macular degeneration (AMD), a leading cause of blindness. By combining mechanistic findings in stem-cell-derived human RPE, in- vivo functional studies in mice and global transcriptomic and proteomic analyses, we revealed that the key developmental transcription factors LHX2 and OTX2 function together in transcriptional module containing LDB1 and SWI/SNF (BAF) to regulate the RPE transcriptome. Importantly, the intersection between the identified LHX2-OTX2 cistrome with published expression quantitative trait loci, ATAC-seq data from human RPE, and AMD GWAS data, followed by functional validation using a reporter assay, revealed a causal genetic variant that affects AMD risk by altering TRPM1 expression in the RPE through modulation of LHX2 transcriptional activity on its promoter. Taken together, the reported cistrome of LHX2 and OTX2, the identified downstream genes and interacting co-factors reveal the RPE transcription module and uncover a causal regulatory risk SNP in the multifactorial common blinding disease AMD.

2023-03-11 | PXD038485 | Pride

A widespread decrease of chromatin accessibility in age-related macular degeneration

Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly. The extent to which epigenetic changes regulate the progression of AMD is unclear. Here we profiled chromatin accessibility in the retina and retinal pigmented epithelium (RPE) from AMD patients and controls. Global decreases in chromatin accessibility occur in the RPE in early AMD and in the retina with advanced disease. Footprints of photoreceptor and RPE-specific transcription factors are enriched in differentially accessible regions (DARs) and reduced AMD. Genes associated with DARs show altered expression in AMD. Cigarette smoke, an established risk factor for AMD, applied to human iPSC-derived RPE cells recapitulates epigenomic changes seen in AMD. In addition to providing a comprehensive profile of chromatin accessibility in human RPE and retina, this study shows that global decreases in chromatin accessibility may play a critical role in AMD progression.

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Age- and sex- divergent translatomic responses of the retinal pigmented epithelium

Project description:Aging is the main risk factor for age-related macular degeneration (AMD), a retinal neurodegenerative syndrome that leads to irreversible blindness, particularly in people over 60 years old. Retinal pigmented epithelium (RPE) atrophy is an AMD hallmark that often precedes photoreceptor loss. Genome-wide chromatin accessibility, DNA methylation, and gene expression studies of AMD and control RPE demonstrate epigenomic/transcriptomic changes occur during AMD onset and progression. However, mechanisms by which molecular alterations of normal aging impair RPE function and contribute to AMD pathogenesis are unclear. Here, we specifically interrogate the RPE translatome with advanced age and across sexes in a novel mouse model. We find differential age- and sex- associated transcript expression with overrepresentation of pathways related to inflammation in the RPE. Concordant with impaired RPE function, the phenotypic changes in the aged translatome suggest that aged RPE becomes immunologically active, in both males and females, with some sex-specific signatures, which supports the need for sex representation for in vivo studies.

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Project description:Complement Factor H (CFH) common genetic variants have been associated with age-related macular degeneration (AMD). While most previous in vitro RPE studies focused on the common p.His402Tyr CFH variant, we characterized rare CFH variants that are highly penetrant for AMD using induced pluripotent stem cell derived retinal pigment epithelium (iPSC-RPE). Our results show that lower FH levels were detected in AMD RPE, which potentially disrupted canonical and non-canonical roles of FH. Specifically, AMD RPE displayed higher inflammation rate and a reduced set of differentially expressed genes compared to control RPE upon A2E and blue light challenge. Additionally, cholesterol efflux and POS phagocytosis defects, dysregulated complement levels, larger sub-RPE deposits and increased mitochondrial stress were observed in AMD RPE. Thus, our study reveals new non-canonical roles for FH in regulating important RPE functions.

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Oxidative stress induces mitochondrial dysfunction and a protective unfolded protein response in RPE cells

Project description:How retinal pigmented epithelial (RPE) cells degenerate from oxidative stress in age-related macular degeneration (AMD) is incompletely understood. The study's intent was to identify key cytoprotective pathways activated by oxidative stress, and to determine the extent of their protection. Immunohistochemistry was used to identify the unfolded protein response (UPR) and mitochondria in the RPE of AMD samples. Maculas with early AMD had prominent IRE1α, but minimal mitochondrial TOM20 immunolabeling in mildly degenerated RPE. RPE cells treated with cigarette smoke extract (CSE), by microarray analysis, had over-represented genes involved in the antioxidant and unfolded protein response, and mitochondrial location. CSE induced the UPR sensors IRE1α, p-PERK, and ATP6, which activated CHOP. CHOP knockdown compromised cell viability after CSE exposure. At the same CSE doses, mitochondria generated superoxide anion and produced less ATP. In mice given intravitreal CSE, the RPE had increased IRE1α and decreased ATP, which elicited RPE epithelial-mesenchymal transition, as suggested by altered ZO1 immunolabeling of RPE flatmounts. Our experiments indicate that RPE cells exposed to oxidative stress respond with a cytoprotective antioxidant and unfolded protein response, but develop mitochondrial impairment that contributed to epithelial mesenchymal transition. With similar responses in the RPE of early AMD samples, these results suggest that mitochondria are vulnerable to oxidative stress while the ER elicits a protective response during early AMD. A total of 9 samples were analyzed: 3 control samples, 3 samples treated with 100ug/ml of Cigarette Smoke Condensate, and 3 samples treated with 250ug/ml of Cigarettes Smoke Condensate.

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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. In this study we investigated changes in differentated human retinal pigmented epithelial (RPE) cells to acute compared to chronic wounding. There are many interesting phenotypic and transcriptomic changes that occur after chronic wounding compared to acute wounding conditions which may have implications for AMD.

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