Time-Dependent Glucocorticoid-Induced Transcriptomic Changes in Human Trabecular Meshwork and Schlemm's Canal Cells.

Area of Science:

• Ophthalmology
• Genomics
• Molecular Biology

Background:

• Glucocorticoids, like dexamethasone (DEX), can increase intraocular pressure (IOP), a major risk factor for primary open-angle glaucoma (POAG).
• Understanding the molecular mechanisms by which DEX affects ocular tissues is crucial for developing targeted therapies.

Purpose of the Study:

• To comprehensively identify transcriptomic changes induced by DEX in human trabecular meshwork (TM) and Schlemm's canal endothelial (SCE) cells using RNA sequencing (RNA-seq).
• To explore the association of DEX-responsive genes with POAG and IOP.

Main Methods:

• Human TM (n=10) and SCE (n=5) cell strains were treated with DEX (100 nM) or vehicle for 1 hour, 6 hours, and 2 days.
• RNA-seq was performed, and differential gene expression analysis (DESeq2) identified DEX-responsive genes (DEGs) at a false discovery rate < 0.05.
• Gene Set Enrichment Analysis (GSEA) and association tests with POAG/IOP were conducted on identified DEGs.

Main Results:

• Significant transcriptomic alterations were observed in both TM and SCE cells following DEX exposure.
• After 2 days, 857 DEGs were found in TM cells and 2086 in SCE cells, with 411 common DEGs, including highly significant FKBP5 and FAM107A.
• DEGs were enriched in pathways related to cell adhesion, extracellular matrix, and response to stimuli; early responses involved immune processes.
• Specific genes like LTBP2 (TM-only) and FAM105A (SCE-only) were associated with IOP and POAG risk.

Conclusions:

• This study provides a detailed transcriptomic profile of DEX effects in TM and SCE cells.
• Identified candidate genes and pathways offer novel insights into glucocorticoid-induced ocular hypertension.
• These findings can inform future human genetic analyses for POAG and steroid-induced glaucoma.