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Xianfang Rong, Xiaodi Qiu, Yi Lu; Histone acetylation modification on SOD1 gene expression in the pathogenesis of human senile cataract. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5602.
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© ARVO (1962-2015); The Authors (2016-present)
Previous studies have shown that histone acetylation of superoxide dismutase 1 (SOD1) gene are closely associated the regulation of oxidative stress, which is one of main causes contribute to onset of senile cataract (SC). We hypothesized that decreased histone acetylation level in SOD1 reduces the gene expression in lens epithelium (LE) and contributes to the pathogenesis of SC.
Cataractous LE was collected from SC patients underwent phacoemulsification. Clear LE was obtained from human donor eyes as control. Level of acetylated histone H3 (ac-H3) and acetylated histone H4 (ac-H4) as well as SOD1 in LE was measured by Western-blot. Expression of SOD1 mRNA transcripts was evaluated by real-time PCR. Level of ac-H3 and ac-H4 in SOD1 promoter was examined by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR). To further demonstrate histone acetylation on regulation of SOD1 expression and onset of SC, enucleated rabbit lenses were maintained in culture DMEM medium alone (group I), supplemented with histone acetyltransferease inhibitor (HATi) anacardic acid (AA) (group II), and AA combined with histone deacetylase inhibitor (HDACi) trichostatin A (TSA) (group III). Lenses opacity formation, SOD1 expression and level of ac-H3 and ac-H4 in SOD1 promoter in cultured lenses’ LE were investigated.
Western-blot analysis did't show significantly different level of total ac-H3 and ac-H4 between cataractous LE and control (P=0.453), while SOD1 expression reduced remarkably (p<0.001) in SC patients. ChIP-qPCR revealed that level of both ac-H3 and ac-H4 in SOD1 promoter decreased profoundly in patients’ LE (p<0.001 for both). Rabbit lenses cultured with AA lost transparency and became opacity at 3 days in group II. Lenses in group I and III still kept transparent during observation. SOD1 protein and mRNA level both decreased in group II compared with group I (p<0.001) and III (p<0.001). Level of ac-H3 and ac-H4 reduced significantly in SOD1 gene promoter of lenses cultured HATi. Lenses supplemented with AA and TSA did not detect any changes of SOD1 expression and histone acetylation.
SOD1 expression decreased with the reduction of ac-H3 and ac-H4 level in SOD1 promoter in SC patients, which contributed to the pathogenesis of SC. HATi could reduce the expression of SOD1, and induce the formation of cataract in vitro. The results were consistent with our hypothesis.
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