title: Global DNA hypomethylation and hypoxia-induced expression of the ten eleven translocation (TET) family, TET1, in scleroderma fibroblasts.
abstract: The precise mechanisms of tissue fibrosis have not yet been elucidated in systemic sclerosis (SSc). 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 SSc. The mRNA levels of TET family members were compared in normal and SSc fibroblasts. The effects of hypoxia and siRNA specific to HIF-1α on TET expression were also examined. Global methylation status was analysed by LUMA. The presence of 5-hydroxymethylcytosine (5hmC) in SSc was examined by immunohistochemistry. The level of TET1 mRNA in SSc fibroblasts was elevated by 1.68 fold compared with that of normal fibroblasts, but the expression levels of TET2 and TET3 were comparable between both cell types. The expression levels of DNMT1 and DNMT3B mRNA have a tendency to elevate in SSc fibroblasts. Among TET family members, the expression of TET1 was exclusively induced by hypoxia via HIF-1α-independent pathways in SSc fibroblasts, but not in normal fibroblasts. The methylation level was decreased in SSc fibroblasts relative to normal fibroblasts, and 5hmC was present in dermal fibroblasts of skin sections from patients with SSc. TET1 expression in SSc 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.
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Hattori
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yokoyama
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.|Hattori Dermatology Clinic, Takasaki, Gunma, Japan.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Sei-Ichiro
authors.initials: S
authors.lastname: Motegi
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Amano
authors.affiliation: Laboratory of Genome Science, Biosignal Genome Resource Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Izuho
authors.initials: I
authors.lastname: Hatada
authors.affiliation: Department of Dermatology, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Ishikawa
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation; D005347:Fibroblasts / Q000201:enzymology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D012595:Scleroderma, Systemic / Q000201:enzymology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006899:Mixed Function Oxygenases; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D000097584:DNA Methyltransferase 3B; C462539:TET1 protein, human; C000619380:DNMT1 protein, human
keywords: DNA methylation; epigenetics; fibroblasts; systemic sclerosis; ten eleven translocation