Abstract
The methyl-CpG-binding domain 2 (MBD2) interprets DNA methylome-encoded information through binding to the methylated CpG DNA, by which it regulates target gene expression at the transcriptional level. Although derailed DNA methylation has long been recognized to trigger or promote autoimmune responses in type 1 diabetes (T1D), the exact role of MBD2 in T1D pathogenesis, however, remains poorly defined. Herein, we generated an Mbd2 knockout model in the NOD background and found that Mbd2 deficiency exacerbated the development of spontaneous T1D in NOD mice. Adoptive transfer of Mbd2−/− CD4 T cells into NOD.scid mice further confirmed the observation. Mechanistically, Th1 stimulation rendered the Stat1 promoter to undergo a DNA methylation turnover featured by the changes of DNA methylation levels or patterns along with the induction of MBD2 expression, which then bound to the methylated CpG DNA within the Stat1 promoter, by which MBD2 maintains the homeostasis of Th1 program to prevent autoimmunity. As a result, ectopic MBD2 expression alleviated CD4 T cell diabetogenicity following their adoptive transfer into NOD.scid mice. Collectively, our data suggest that MBD2 could be a viable target to develop epigenetic-based therapeutics against T1D in clinical settings.
Highlights
Type 1 diabetes (T1D) is a chronic autoimmune disease resulting from T cell-mediated pancreatic islet β cell destruction [1]
It was interestingly noted that Mbd2−/− NOD mice exhibited increased infiltration of lymphocytes in the salivary gland, a feature prior to the development of Sjogren’s syndrome [20], but no evident inflammatory infiltration was observed in the colon, lung, kidney, liver, or heart (Fig. S1)
Those results indicate that loss of Mbd2 exacerbates lymphoid infiltration and T1D onset in NOD mice
Summary
Type 1 diabetes (T1D) is a chronic autoimmune disease resulting from T cell-mediated pancreatic islet β cell destruction [1]. DNA methylation, one of the critical epigenetic mechanisms associated with the regulation of gene transcription, has been recognized to be involved in T1D pathogenesis [11, 12]. B Plasma c-peptide levels in 8–12 weeks old pre-diabetic female WT and Mbd2−/− NOD mice (n = 7 per group). C Representative picture of the spleen and pancreatic draining lymph nodes of 8-week-old prediabetic female WT and Mbd2−/− NOD mice (4 mice per group). Insulitis was examined (D) and scored (E) in 5–6 and 12–15-week-old prediabetic female WT and Mbd2−/− NOD mice respectively. MBD2 selectively binds to the methylated CpG DNA in the Stat promoter, by which it represses STAT1-IFN-γ signaling to maintain the homeostasis of the Th1 program, and similar results were obtained in T1D patients as well. Our findings shed new light on the role of MBD2 in T1D pathogenesis, which could pave the way to develop epigeneticbased therapies against T1D in clinical settings
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