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

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. Overall design: In the study, we profiled chromatin accessibility using ATAC-Seq (Assay for Transposase-Accessible Chromatin with high throughput sequencing) in 26 retinas and 20 RPE samples including one replicate. These samples are from fresh postmortem eyes which are healthy, early-stage AMD or late-stage AMD. Meanwhile, we profiled gene expression using RNA-Seq in 4 samples from retina and RPE tissues of one AMD patient whose right and left eyes are at early stage and late stage of AMD diease, respectively. In addition, we performed ATAC-seq in human RPE cell lines.