HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFbeta2 in the Trabecular Meshwork

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dc.creatorBermudez, Jaclyn Y.
dc.creatorWebber, Hannah C.
dc.creatorPatel, Gaurang C.
dc.creatorLiu, Xiangyang
dc.creatorCheng, Yi-Qiang
dc.creatorClark, Abbot F.
dc.creatorMao, Weiming
dc.creator.orcid0000-0001-9336-2593 (Cheng, Eric Yi-Qiang)
dc.creator.orcid0000-0003-3594-6560 (Clark, Abbot F.)
dc.date.accessioned2022-08-25T19:58:38Z
dc.date.available2022-08-25T19:58:38Z
dc.date.issued2016-07-01
dc.description.abstractPURPOSE: Elevated intraocular pressure (IOP) in primary open-angle glaucoma (POAG) results from glaucomatous damage to the trabecular meshwork (TM). The glaucoma-associated factor TGFbeta2 is increased in aqueous humor and TM of POAG patients. We hypothesize that histone acetylation has a role in dysregulated TGFbeta2 expression. METHODS: Protein acetylation was compared between nonglaucomatous TM (NTM) and glaucomatous TM (GTM) cells using Western immunoblotting (WB). Nonglaucomatous TM cells were treated with 10 nM thailandepsin-A (TDP-A), a potent histone deacetylase inhibitor for 4 days. Total and nuclear proteins, RNA, and nuclear protein-DNA complexes were harvested for WB, quantitative PCR (qPCR), and chromatin immunoprecipitation (ChIP) assays, respectively. Paired bovine eyes were perfused with TDP-A versus DMSO, or TDP-A versus TDP-A plus the TGFbeta pathway inhibitor LY364947 for 5 to 9 days. Intraocular pressure, TM, and perfusate proteins were compared. RESULTS: We found increased acetylated histone 3 and total protein acetylation in the GTM cells and TDP-A treated NTM cells. Chromatin immunoprecipitation assays showed that TDP-A induced histone hyperacetylation associated with the TGFbeta2 promoter. This change of acetylation significantly increased TGFbeta2 mRNA and protein expression in NTM cells. In perfusion-cultured bovine eyes, TDP-A increased TGFbeta2 in the perfusate as well as elevated IOP. Histologic and immunofluorescent analyses showed increased extracellular matrix and cytoskeletal proteins in the TM of TDP-A treated bovine eyes. Cotreatment with the TGFbeta pathway inhibitor LY364947 blocked TDP-A-induced ocular hypertension. CONCLUSIONS: Our results suggest that histone acetylation has an important role in increased expression of the glaucoma-associated factor TGFbeta2. Histone hyperacetylation may be the initiator of glaucomatous damage to the TM.
dc.description.sponsorshipSupported by the Thomas R. Lee award for National Glaucoma Research (G2011032), a program of the Bright Focus Foundation (WM), National Eye Institute R21EY023048 (WM), UNTHSC faculty seed grant (WM), a research grant provided by Cure Glaucoma Foundation (WM), National Cancer Institute CA152212 (Y-QC), and NIH training grant in the Neurobiology of Aging (T32 AG20494; JYB).
dc.identifier.citationBermudez, J. Y., Webber, H. C., Patel, G. C., Liu, X., Cheng, Y. Q., Clark, A. F., & Mao, W. (2016). HDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFβ2 in the Trabecular Meshwork. Investigative ophthalmology & visual science, 57(8), 3698-3707. https://doi.org/10.1167/iovs16-19446
dc.identifier.issn1552-5783
dc.identifier.issue8
dc.identifier.urihttps://hdl.handle.net/20.500.12503/31658
dc.identifier.volume57
dc.publisherARVO Journals
dc.relation.urihttps://doi.org/10.1167/iovs16-19446
dc.rights.holderCopyright 2016 the Authors
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceInvestigative Ophthalmology & Visual Science
dc.subject.meshAcetylation
dc.subject.meshAnimals
dc.subject.meshCattle
dc.subject.meshCells, Cultured
dc.subject.meshEpigenesis, Genetic / genetics
dc.subject.meshGlaucoma, Open-Angle / genetics
dc.subject.meshHistone Deacetylase Inhibitors / pharmacology
dc.subject.meshPyrazoles / pharmacology
dc.subject.meshPyrroles / pharmacology
dc.subject.meshRNA, Messenger / metabolism
dc.subject.meshTrabecular Meshwork / physiology
dc.subject.meshTransforming Growth Factor beta2 / genetics
dc.titleHDAC Inhibitor-Mediated Epigenetic Regulation of Glaucoma-Associated TGFbeta2 in the Trabecular Meshwork
dc.typeArticle
dc.type.materialtext

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