title: Ultraviolet-B induces ERCC6 repression in lens epithelium cells of age-related nuclear cataract through coordinated DNA hypermethylation and histone deacetylation.
abstract: BACKGROUND
  Ultraviolet-B (UVB) exposure attributes to the formation of age-related nuclear cataract (ARNC), which is mediated with DNA damage. DNA damage, an important factor for pathogenesis of ARNC, is induced by UVB, and is generally resolved by the nucleotide excision repair (NER) repair mechanism. Cockayne syndrome complementation group B (CSB) protein coded by ERCC6 is a vital component for NER. However, we found no association between selected ERCC6 polymorphisms and ARNC. In this study, we investigated whether UVB exposure could alter ERCC6 expression and the process could involve epigenetic changes of DNA methylation and/or histone acetylation of ERCC6 in the lens epithelial cells (LECs). We also assessed the involvement of those coordinated changes in lens tissue from ARNC patients.
  
  
  RESULTS
  mRNA and protein expression of ERCC6 in lens tissue (LECs) were lower in ARNCs than those in the controls. This reduction corresponded to methylation of a CpG site at the ERCC6 promoter and histone modifications (methylation and acetylation) nearby this site. UVB-treated human lens epithelium B3 (HLE-B3) and 239T cell presented (1) increased apoptosis, suggesting reduced UV-damage repair, (2) hypermethylation of the CpG site located at position -441 (relative to transcription start site) within the binding region for transcriptional factor Sp1 in the ERCC6 promoter, (3) the enhancement of histone H3K9 deacetylation, (4) induction in DNA methyltransferases 3b (DNMT3b) and histone deacetylase1 (HDAC1) associated to the CpG site of ERCC6 by CHIP assay.
  
  
  CONCLUSIONS
  These findings suggest an orchestrated mechanism triggered by UVB radiation where the concurrent association of specific hypermethylation CpG site, H3K9 deacetylation of ERCC6, and repression of ERCC6 gene expression. Taken together, with the similar changes in the lens tissue from ARNC patients, our data unveiled a possible mechanism of epigenetic modification of DNA repair gene in the pathogenesis of ARNC.
authors.affiliation: Eye Institute, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ophthalmology Department, Chengdu Fifth People's Hospital, Chengdu, Sichuan China.
authors.forename: Fei
authors.initials: F
authors.lastname: Li
authors.affiliation: Eye Institute, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Eye Institute, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Kang
authors.affiliation: Eye Institute, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu China.
authors.forename: Huaijin
authors.initials: H
authors.lastname: Guan
mesh_terms: D000107:Acetylation / Q000528:radiation effects; D000368:Aged; D002386:Cataract / Q000209:etiology / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D004265:DNA Helicases / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000528:radiation effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D005260:Female; D015870:Gene Expression / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology* / Q000378:metabolism / Q000528:radiation effects; D008297:Male; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins
chemical_list: D006657:Histones; D000075223:Poly-ADP-Ribose Binding Proteins; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes
keywords: Age-related nuclear cataract (ARNC); DNA methylation; ERCC6; Histone deacetylation; Lens epithelial cells (LECs); Sp1; Ultraviolet (UV)