EPIGENETIC REGULATION OF TRANSFORMING GROWTH FACTOR BETA 2 IN THE GLAUCOMA TRABECULAR MESHWORK
Jaclyn Bermudez1Hannah Webber1, Yi-Qiang Cheng, Abbot Clark, Weiming Mao.
University of North Texas Health Science Center, Fort Worth, TX.
The role of epigenetic regulation in glaucoma, an age-related neurodegenerative disease that leads to vision loss and irreversible blindness in millions worldwide, is unknown. The most important risk factor of primary open angle glaucoma (POAG), is elevated intraocular pressure (IOP). IOP elevation in glaucoma patients is due to compromised trabecular meshwork (TM) function. In the glaucoma TM (GTM), transforming growth factor β2 (TGFβ2) is elevated, which disrupts TM homeostasis. We hypothesize that histone acetylation, an epigenetic regulatory mechanism, is responsible for the increased expression of TGFβ2 in the GTM. To test our hypothesis, we treated TM cells with 10 nM thailandepsin-A (TDP-A), a histone deacetylase inhibitor (HDACi), or DMSO (vehicle control) for 4 days. Q-PCR was used to compare gene expression. We also perfusion cultured bovine anterior segments with DMSO or TDP-A for 7 to 10 days. Some eyes were treated with TDP-A or TDP-A plus TGFβ2 associated pathway inhibitor. The IOPs of the bovine eyes were continuously monitored. We found that TDP-A elevated the expression of TGFβ2 in TM cell cultures (n = 6, p < 0.05). Also, TDP-A significantly elevated IOP in perfusion cultured bovine eyes (n = 8, p < 0.05). Furthermore, use of the pathway inhibitor decreased TDP-A induced ocular hypertension. Therefore, we believe histone acetylation may play an important role in the dysregulation of TGFβ2 in the GTM. This mechanism provides a unique opportunity to elucidate the etiology of POAG. We also showed that TDP-A is a potent HDACi that can be used as a powerful tool in glaucoma research.