Epigenetic regulation of TGFβ2 in the pathogenesis of glaucoma

Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The primary risk factor for the development and progression of this optic neuropathy is increased intraocular pressure (IOP) caused by glaucomatous damage to the trabecular meshwork (TM). The glaucoma-associated factor, transforming growth factor beta 2 (TGFβ2) is increased in the TM of POAG patients. TGFβ2 elevates IOP in perfusion cultured human eyes and in rodents. We hypothesize that histone acetylation plays a role in dysregulated TGFβ2 expression. To test our hypothesis, we treated primary non-glaucomatous human TM (NTM) cells as well as perfusion cultured bovine eyes with 10 nM thailandepsin-A (TDP-A), a potent histone deacetylase inhibitor. We found that TDP-A increased protein acetylation in the TM using Western immunoblotting. Chromatin immunoprecipitation showed that TDP-A induced histone hyperacetylation associated with the TGFβ2 promoter. This change of acetylation significantly increased TGFβ2 expression in NTM cells as shown by quantitative PCR (n=6, p