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Xuesen Cheng, Qingnan Liang, Jun Wang, Leah A Owen, Yumei Li, Margaret M DeAngelis, Rui Chen; A single cell multi-omics atlas of the human retina. Invest. Ophthalmol. Vis. Sci. 2022;63(7):2311.
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© ARVO (1962-2015); The Authors (2016-present)
The human retina, as part of the central nerve system and the key light sensing tissue in the eye, has high cell heterogeneity, with an estimate of over 60 distinct cell types distinguished by morphology and physiology. To better understand the gene expression and regulation in each cell type, our study generates the multi-omics atlas at the single-cell level for adult human retina.
Single-nuclei RNA-seq and single-nuclei ATAC-seq were performed for retinae from human donors using the 10x Genomics technologies. For each donor retina, both the fovea and peripheral regions are profiled. Rare cell types, including the amacrine and retinal ganglion cell, are enriched based on the NeuN gradient. Integrative analysis of transcriptomic and epigenomic data is performed to identify gene regulator networks (GRNs), transcriptional factor binding motif enrichment, and putative gene cis-regulatory elements.
A large single nuclei multi-omics dataset containing over 250K cells with single-nuclei RNA-seq and over 150K cells with single-nuclei ATAC-seq from human adult retina was generated. The atlas contains over 60 distinct cell types with an estimated sensitivity of 0.01%. Cross-species comparison among human, monkey, and mouse retina reveals that cell subtypes are overall conserved with RGCs are most divergent. In contrast, significant difference is observed at the transcriptomic level in corresponding cell types. With a large-scale single-nuclei ATAC-seq, we uncovered 10 times more open chromatin regions than the bulk study. Many of these regions are specific for rare cell types and were not observed in bulk ATAC-seq data. By combining snRNA/ATAC-seq data, 18% of these open chromatin regions (~47K) can be linked to their target genes as putative regulatory elements. Strikingly, a significant portion of these cis regulatory elements are novel and show cell-type-specific activity. Finally, the single nuclei multi-omics data allows fine mapping and functional annotation of genomic variants through integration of eQTL and GWAS results.
Our study represents the most comprehensive transcriptome and epigenome atlas of the human retina to date. This atlas enables in-depth integrative analysis at individual cell type resolution, making it a highly valuable resource for the research community.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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