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Colm J. O'Brien, Fiona McDonnell, Abbot F. Clark, Deborah M. Wallace; Differential Expression of Key Epigenetic Re-programming Genes in Human Lamina Cribrosa Cells in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2810.
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Current treatment for glaucoma focuses on lowering of intraocular pressure (IOP), but despite apparently well controlled IOP some patients continue to suffer progressive damage and the cause of this observation remains unknown. Epigenetics refers to heritable changes in gene expression or cell phenotype caused by mechanisms other than changes in the underlying DNA sequence, for example, DNA modifications such as methylation or histone deacetylation. Local environmental factors such as tissue hypoxia are known to result in global epigenetic modifications/programming of the human genome. The purpose of this study is to investigate the expression of key genes involved in epigenetic re-programming in lamina cribrosa (LC) cells obtained from normal and glaucomatous donors.
Total RNA was extracted from LC cells isolated from glaucomatous and normal donors and reverse transcribed to cDNA. Quantitative real-time PCR was subsequently performed using gene specific exon-exon spanning primers to DNA (cytosine-5)-methyltransferase 1 (DNMT1), P300/CBP-associated factor (PCAF), Histone deacetylase 7 (HDAC7), Histone deacetylase 1 (HDAC 1) and the tumour suppressor p53 which can affect DNA binding capacity, histone acetylation and DNA methylation. Gene expression rates were compared using 18s rRNA normalized threshold cycle number values (cT’s). The equation 2^-ΔcT was used to derive a fold difference in gene expression.
Importantly, genes involved in the maintenance of DNA methylation (DNMT1) and acetylation (PCAF, HDAC7 and HDAC 1) status are significantly increased (P<0.05) in LC cells isolated from glaucomatous donors. Interestingly levels of tumour suppressor gene p53 were also up regulated; p53 itself can be acetylated and also has a function in oxidative stress and autophagy.
These data support our hypothesis that aberrant epigenetic modification occurs in human optic nerve head LC cells in glaucoma. Further studies will include investigation of differential epigenetic gene expression profiles in trabecular meshwork (TM) cells with the goal of exploring the potential of novel therapies such as HDAC inhibitors in the management of glaucoma.
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