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TLR2-ICAM1-Gadd45α Axis Mediates the Epigenetic Effect of Selenium on DNA Methylation and Gene Expression in Keshan Disease

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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.

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Acknowledgments

This work was supported by the Chinese national natural science fund project approval (NO-30972557), (NO-81170290).

Authorship

Xiaolin Niu and Jin Wei conceived and designed the study. Guang Yang performed the experiment, analyzed and interpreted the data, and wrote the initial draft of the manuscript. Yanhe Zhu, Xin Dong, and Zongming Duan contributed to the experimental design, the statistical analysis, and the writing of the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 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

    Guang Yang, Yanhe Zhu, Xin Dong, Zongming Duan, Xiaolin Niu & Jin Wei

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  1. Guang Yang
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Correspondence to Xiaolin Niu.

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Yang, G., Zhu, Y., Dong, X. et al. TLR2-ICAM1-Gadd45α Axis Mediates the Epigenetic Effect of Selenium on DNA Methylation and Gene Expression in Keshan Disease. Biol Trace Elem Res 159, 69–80 (2014). https://doi.org/10.1007/s12011-014-9985-8

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