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Global DNA hypomethylation and hypoxia‐induced expression of the ten eleven translocation ( TET ) family, TET 1, in scleroderma fibroblasts
Author(s) -
Hattori Mai,
Yokoyama Yoko,
Hattori Tomoyasu,
Motegi Seiichiro,
Amano Hiroo,
Hatada Izuho,
Ishikawa Osamu
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12767
Subject(s) - dna methylation , microbiology and biotechnology , fibroblast , methylation , epigenetics , biology , messenger rna , pathogenesis , gene expression , dna , cell culture , gene , immunology , genetics
The precise mechanisms of tissue fibrosis have not yet been elucidated in systemic sclerosis ( SS c). However, studies of the regulation of DNA methylation, the most widely studied epigenetic mechanism, have confirmed the involvement of the TET family proteins, recently identified DNA demethylases, in the pathogenesis of SS c. The mRNA levels of TET family members were compared in normal and SS c fibroblasts. The effects of hypoxia and si RNA specific to HIF ‐1 α on TET expression were also examined. Global methylation status was analysed by LUMA . The presence of 5‐hydroxymethylcytosine (5hmC) in SS c was examined by immunohistochemistry. The level of TET 1 mRNA in SS c fibroblasts was elevated by 1.68 fold compared with that of normal fibroblasts, but the expression levels of TET 2 and TET 3 were comparable between both cell types. The expression levels of DNMT 1 and DNMT 3B mRNA have a tendency to elevate in SS c fibroblasts. Among TET family members, the expression of TET 1 was exclusively induced by hypoxia via HIF ‐1 α ‐independent pathways in SS c fibroblasts, but not in normal fibroblasts. The methylation level was decreased in SS c fibroblasts relative to normal fibroblasts, and 5hmC was present in dermal fibroblasts of skin sections from patients with SS c. TET 1 expression in SS c fibroblasts was abnormally regulated in the hypoxic environment and accompanied by global DNA hypomethylation, suggesting the involvement of aberrant DNA methylation in the pathogenesis of SSc.