Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4+ T cells of systemic lupus erythematosus

Publication date: Available online 4 November 2017
Source:Clinical Immunology
Author(s): Ming Zhao, Meng-ying Li, Xiao-fei Gao, Su-jie Jia, Ke-qin Gao, Yin Zhou, Hui-hui Zhang, Yi Huang, Jing Wang, Hai-jing Wu, Qian-jin Lu
DNA hypomethylation plays an important role in the pathogenesis of systemic lupus erythematosus (SLE). Here we investigated whether 3-hydroxy butyrate dehydrogenase 2 (BDH2), a modulator of intracellular iron homeostasis, was involved in regulating DNA hypomethylation and hyper-hydroxymethylation in lupus CD4⁺ T cells. Our results showed that BDH2 expression was decreased, intracellular iron was increased, global DNA hydroxymethylation level was elevated, while methylation level was reduced in lupus CD4⁺ T cells compared with healthy controls. The decreased BDH2 contributed to DNA hyper-hydroxymethylation and hypomethylation via increasing intracellular iron in CD4⁺ T cells, which led to overexpression of immune related genes. Moreover, we showed that BDH2 was the target gene of miR-21. miR-21 promoted DNA demethylation in CD4⁺ T cells through inhibiting BDH2 expression. Our data demonstrated that the dysregulation of iron homeostasis in CD4⁺ T cells induced by BDH2 deficiency contributes to DNA demethylation and self-reactive T cells in SLE.



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