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Age-related macular degeneration (AMD) mitochondria modulate epigenetic mechanisms in retinal pigment epithelial cells.

ABSTRACT: Mitochondrial damage and epigenetic modifications have been implicated in the pathogenesis of Age-related Macular Degeneration (AMD). This study was designed to investigate the effects of AMD/normal mitochondria on epigenetic regulation in human transmitochondrial retinal pigment epithelial (RPE) cells in vitro. Human RPE cybrid cell lines were created by fusing mitochondria-deficient (Rho0) ARPE-19?cells with platelets obtained from either AMD patients (AMD cybrids) or normal subjects (normal cybrids). Therefore, all cybrids had identical nuclei (derived from ARPE-19?cells) but mitochondria derived from either AMD patients or age-matched normal subjects. AMD cybrids demonstrated increased RNA/protein levels for five methylation-related and four acetylation-related genes, along with lower levels of two methylation and three acetylation genes compared to normal cybrids. Demethylation using 5-Aza-2'-deoxycytidine (DAC) led to decreased expression of VEGF-A gene in AMD cells. Trichostatin A (TSA), an HDAC inhibitor, also influenced protein levels of VEGF-A, HIF1?, NF?B, and CFH in AMD cells. Our findings suggest that retrograde signaling leads to mitochondria-nucleus interactions that influence the epigenetic status of the RPE cells and this may help in the identification of future potential therapeutic targets for AMD.

SUBMITTER: Nashine S

PROVIDER: S-EPMC7192350 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Age-related macular degeneration (AMD) mitochondria modulate epigenetic mechanisms in retinal pigment epithelial cells.

Nashine Sonali S Nesburn Anthony B AB Kuppermann Baruch D BD Kenney M Cristina MC

Experimental eye research 20190619

Mitochondrial damage and epigenetic modifications have been implicated in the pathogenesis of Age-related Macular Degeneration (AMD). This study was designed to investigate the effects of AMD/normal mitochondria on epigenetic regulation in human transmitochondrial retinal pigment epithelial (RPE) cells in vitro. Human RPE cybrid cell lines were created by fusing mitochondria-deficient (Rho0) ARPE-19 cells with platelets obtained from either AMD patients (AMD cybrids) or normal subjects (normal c ...[more]

PMID: 31226340

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Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control M-bM-^IM-% median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD. Using AltAnalyze (ver. 2.0.7 beta), we analyzed nine early AMD and nine control eyes using Affymetrix Human Exon ST 1.0 arrays. Following initial processing in AltAnalyze, two control arrays were identified as potential outliers by tests implement in arrayQualityMetrics, a package for R.

Project description:Purpose: Age-related degeneration (AMD) is a major cause of blindness in developed countries. The molecular pathogenesis of early events in AMD is poorly understood. We investigated differential gene expression in samples of human retinal pigment epithelium (RPE)/choroid from early AMD and control maculas using exon-based arrays. Methods: Gene expression levels in nine early AMD and nine control human donor eyes were assessed using Affymetrix Human Exon ST 1.0 arrays. Two controls did not pass quality control and were removed. Differentially expressed genes were annotated using DAVID, and gene set enrichment analysis (GSEA) was performed on RPE-specific and endothelium-associated gene sets. CFH genotype was also assessed and differential expression was analyzed with respect to high AMD risk (YH/HH) and low AMD risk (YY) genotypes. Results: Seventy-five genes were identified as differentially expressed (raw p-value < 0.01; >50% fold change, mean log2 expression level in AMD or control ≥ median of all average gene expression values); however, no genes were significant (adj. p-value < 0.01) after correction for multiple hypothesis testing. Of 52 genes with decreased expression in AMD (fold change < 0.5; raw p-value < 0.01), 18 genes were identified by DAVID analysis as associated with vision or neurological processes. GSEA of RPE-associated and endothelium-associated genes revealed a significant decrease in genes typically expressed by endothelial cells in the early AMD group compared to controls, consistent with previous histologic and proteomic studies. Analysis with respect to CFH genotype indicated decreased expression of ADAMTS9 in eyes with high-risk genotypes (fold change = -2.61; raw p-value = 0.0008). Conclusions: GSEA results suggest that RPE transcripts are preserved or elevated in early AMD, concomitant with loss of endothelial cell marker expression. These results are consistent with the notion that choroidal endothelial cell dropout occurs early in the pathogenesis of AMD.

Dataset Information

Age-related macular degeneration (AMD) mitochondria modulate epigenetic mechanisms in retinal pigment epithelial cells.

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Age-related macular degeneration (AMD) mitochondria modulate epigenetic mechanisms in retinal pigment epithelial cells.

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