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Altered Expression and DNA Methylation Profiles of ERCC6 Gene in Lens Tissue from Age-Related Cortical Cataract

Yong Wang, Guowei Zhang, Fei Li, Lihua Kang, Jindong Ben, Han Rong, and Huaijin Guan

Ultraviolet (UV)-induced DNA damage attributes to the pathogenesis of age-related cataract (ARC) and is repaired via the nucleotide excision repair (NER). It is known that Cockayne syndrome complementation group B (CSB) protein coded by ERCC6 is a component of NER complex. DNA methylation is one of the major epigenetic events and is catalyzed by DNA 5-cytosine-methyltransferases (DNMTs). This study was to examine the potential contribution of DNA methylation of CpG islands in ERCC6 promoter region in lens tissues to ARC pathogenesis. Fifteen cortical type of ARC lenses and fifteen transparent lenses from human subjects were included in this study. ERCC6 and DNMTs expression in the lenses were analyzed by qRT-PCR and western blot. Bisulfite-sequencing PCR (BSP) was performed to evaluate methylation status of ERCC6. An in-vitro experiment by adding a demethylating agent 5-aza-2’-deoxycytidine (5-aza-dC) in Human lens epithelium B-3 (HLE B-3) was conducted to confirm the role of DNA methylation in ERCC6 expression. The results show that the mRNA and protein levels of ERCC6 were significantly reduced in the LECs and lens cortex of ARCs. DNMT3b mRNA was significantly higher in LECs of ARCs than that of the controls. In ARC group, the CpG island in the promoter region of ERCC6 displayed hypermethylation in LECs compared to that of the controls. After treatment with 5-aza-dC, the ERCC6 protein level increased in HLE B-3. We concluded that the overexpression of DNMT3b in lens is associated to the hypermethylation of the CpG island of ERCC6, which linked to the reduced ERCC6 expression in LECs from ARC patients. This epigenetic change in ERCC6 gene might be a factor of ARC formation that is mediated with impaired DNA repair.