title: TLR2-ICAM1-Gadd45α axis mediates the epigenetic effect of selenium on DNA methylation and gene expression in Keshan disease.
abstract: Keshan disease (KD) is a fatal dilated cardiomyopathy with unknown etiology, and selenium deficiency is considered the main cause of KD. Several observations implicate a role for altered DNA methylation in selenium deficiency-related diseases. The aim of the present study was to investigate the epigenetic effects of selenium (Se) on DNA methylation and gene expression in Keshan disease. Using methylated DNA immunoprecipitation chip (MeDIP-Chip) and quantitative RT-PCR, we identified two inflammatory-related genes (TLR2 and ICAM1) that were differentially methylated and expressed between normal individuals and KD patients. Results from DNA methylation profile between KD patients and normal individuals showed that selenium deficiency decreased methylation of CpG islands in promoter regions of TLR2 and ICAM1 and upregulated messenger RNA (mRNA) and protein levels of TLR2 and ICAM1. In rat animal model of Keshan disease, selenite treatment could increase TLR2 and ICAM1 promoter methylation, suppress these genes expression, and reduce infiltration of myocardial inflammatory cells. In cell culture model of Keshan disease, we found 5-Aza-dC (DNMT1 inhibitor) treatment in the presence of selenium-reduced mRNA and protein levels of DNMT1 regardless of TLR2 and ICAM1 promoter methylation status and expression levels of these genes. Selenite treatment suppressed the expression of the Gadd45α, TLR2, and ICAM1 in a concentration-dependent manner, while selenium deficiency increased the expression of the Gadd45α, TLR2, and ICAM1 and decreased TLR2 and ICAM1 promoter methylation level in a time-dependent manner. Our results revealed that TLR2-ICAM1-Gadd45α axis might play an important role in gene-specific active DNA demethylation during inflammatory response in myocardium.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital, Key Laboratory of Environment and Genes Related to Diseases of Education Ministry, Xi'an Jiaotong University School of Medicine, Xi'an, Shaanxi, 710004, People's Republic of China.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.forename: Yanhe
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Zongming
authors.initials: Z
authors.lastname: Duan
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Niu
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
mesh_terms: D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics; D004769:Enterovirus Infections / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D051381:Rats; D012643:Selenium / Q000633:toxicity*; D051195:Toll-Like Receptor 2 / Q000235:genetics* / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins; D018799:Intercellular Adhesion Molecule-1; D009687:Nuclear Proteins; D012643:Selenium; D051195:Toll-Like Receptor 2; C439070:GADD45A protein, human; D000097642:GADD45 Proteins