Chromatin dynamics secondary to dexamethasone exposure identifies 67 genes linked to elevated IOP and primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a chronic neurodegenerative disorder, and elevated intraocular pressure (IOP) represents its only modifiable risk factor. We modeled increased IOP by treating three primary human trabecular meshwork cell strains with dexamethasone and generated a high-resolution map of promoter-centered chromatin contacts and regulatory modules. We identify dynamic changes in chromatin compartments and looping, cis-regulatory elements, and transcription factor hubs corresponding to altered expression profile. By integrating Genomewide association studies associated variants with dexamethasone induced chromatin landscape, we ascertain 29 target genes linked to 23 lead IOP variants and 57 genes for 46 POAG variants, with 19 shared between the two. Pathway analysis of 67 IOP- and POAG-associated genes reveals enrichment in vesicle transport, TLR, MAPK, and hippo-YAP signaling pathways. We also uncover transcriptional regulatory role of 103 noncoding lead variants. Our studies provide a mechanistic framework of genetic complexity accompanying steroid-induced IOP and related POAG pathology.