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

Clin Immunol. 2018 Feb;187:113-121. doi: 10.1016/j.clim.2017.11.002. Epub 2017 Nov 4.

Abstract

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.

Keywords: DNA hydroxymethylation; DNA methylation; Iron homeostasis; Systemic lupus erythematosus; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / metabolism*
  • Case-Control Studies
  • DNA Demethylation
  • DNA Methylation
  • Down-Regulation
  • Epigenesis, Genetic
  • Female
  • Gene Knockdown Techniques
  • HEK293 Cells
  • Homeostasis
  • Humans
  • Hydroxybutyrate Dehydrogenase / metabolism*
  • Iron / metabolism*
  • Lupus Erythematosus, Systemic / genetics*
  • Lupus Erythematosus, Systemic / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • MicroRNAs / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Young Adult

Substances

  • MIRN-21 microRNA, mouse
  • MIRN21 microRNA, human
  • MicroRNAs
  • Iron
  • BDH2 protein, human
  • Hydroxybutyrate Dehydrogenase