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Effects of zinc supplementation in the temporal transcriptomic profiling of human primary fetal RPE cell using single-cell RNA sequencing

ABSTRACT: This is the first publication that assessed the complex molecular changes that underpin acute zinc supplementation-induced changes at the single cell RNA sequencing level in a well-characterised age-related macular degeneration (AMD) cell model. The retinal pigment epithelial (RPE) cells were allowed to mature for up to 19 weeks, during which time they developed sub-RPE deposits, a hallmark of AMD. Comparing the scRNA-Seq data from cells after two-, nine- and 19 weeks in culture, we identified distinct clusters of cells. Pseudotemporal ordering of the combined gene lists from all time points identified genes implicated in the dynamics of RPE cell differentiation, with enrichment in biologically plausible pathways. Acute (1 week) zinc supplementation (125 µM added zinc) resulted in the differential expression of several genes, including specific transcriptional regulators.

ORGANISM(S): Homo sapiens

PROVIDER: GSE209758 | GEO | 2023/07/26

REPOSITORIES: GEO

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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.

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Effects of zinc supplementation in the temporal transcriptomic profiling of human primary fetal RPE cell using single-cell RNA sequencing

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