Abstract
Age-related macular degeneration (AMD) predominantly affects the retina and retinal pigment epithelium in the posterior eye. While there are numerous studies investigating the non-coding transcriptome of retina and RPE, few significant differences between AMD and normal tissues have been reported. Strand specific RNA sequencing of both peripheral retina (PR) and RPE-Choroid-Sclera (PRCS), in both AMD and matched normal controls were generated. The transcriptome analysis reveals a highly significant and consistent impact on anti-sense transcription as well as moderate changes in the regulation of non-coding (sense) RNA. Hundreds of genes that do not express anti-sense transcripts in normal PR and PRCS demonstrate significant anti-sense expression in AMD in all patient samples. Several pathways are highly enriched in the upregulated anti-sense transcripts—in particular the EIF2 signaling pathway. These results call for a deeper exploration into anti-sense and noncoding RNA regulation in AMD and their potential as therapeutic targets.
Highlights
Transcriptome studies have generated significant interest in the role of ncRNAs in the maintenance of cellular processes and function
A clear delineation between the peripheral human retina (PR) and peripheral RPE-Choroid-Scleral (PRCS) is observed between tissues, based on sense expression, for both coding and noncoding regions
As far as we are aware, this is the first demonstration of a consistent and dramatic global effect on antisense transcription that is associated with a disease state in humans and is important information to provide the macular degeneration research community
Summary
Transcriptome studies have generated significant interest in the role of ncRNAs in the maintenance of cellular processes and function. Transcriptome studies over the last two decades analyzed the posterior region of the eye using SAGE, microarrays and RNA Sequencing methodologies[19,20,21,22,23] None of these studies have addressed the differences in the transcriptome expression between the normal and AMD retinal tissues. Peripheral human retina (PR) and peripheral RPE-Choroid-Scleral (PRCS) tissues (from normal and AMD donors) were high throughput RNA sequenced to identify unknown transcripts, and quantify transcripts of coding and noncoding RNA that is not possible with microarrays or SAGE23,30–32. Strand-specific sequencing revealed a considerable amount of differential anti-sense transcription of protein coding genes with significant enrichment of several pathways. This high level of differential anti-sense expression suggests its potential functional and clinical relevance in AMD. In accordance with these findings, the focus of this paper is two-fold: an investigation of the non-coding RNA and anti-sense transcription in AMD as compared to normal
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