Abstract
Purpose :
Primary open-angle glaucoma (POAG) is a complex optic neurodegenerative disorder and the second leading cause of blindness. Risk factors for the disease includes age, genetic variants, and elevated intraocular pressure (IOP). Elevated IOP is frequently due to impairment of the trabecular meshwork, a structure that controls aqueous humor outflow from the anterior chamber of the eye. Although genome-wide association studies (GWAS) have identified more than 100 risk loci and associated variants, it remains difficult to link these polymorphisms to potential target genes in relevant ocular tissues. To address this challenge, we have comprehensively characterized the regulatory landscape of the trabecular meshwork cells (TMCs) derived from three adult post-mortem eye donors.
Methods :
Using TMC samples, we generate the regulatory landscape of the non-coding genome by performing CUT&RUN for eight epigenetic marks, define chromatin loops contacting target gene promoters by promoter capture Hi-C, and identify open-chromatin regions of the genome via ATAC-seq.
Results :
We identify over 160,000 chromatin loops including 104,340 loops in contact with specific gene promoters. By intersecting these loops with previously described POAG GWAS variants, we have uncovered physical contacts between genomic regions containing 48 POAG-associated SNPs and 83 gene promoters via chromatin looping. These include 116 loops connecting 46 SNPs to 74 distal gene promoters.
Conclusions :
This powerful approach allows us to both confirm previously proposed connections between SNPs and particular genes as well as propose novel genes which may contribute to POAG progression.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.