Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of Hdac3 on T1DM progression. The expression of miR-296-5p and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-α (TNF-α)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between miR-296-5p and Bcl-xl was verified by using dual-luciferase reporter gene assay, and the binding between Hdac3 and the promoter region of miR-296-5p was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. miR-296-5p expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between miR-296-5p and Bcl-xl in mouse TE15 B lymphocytes. Bcl-xl was further validated to be targeted and negatively regulated by miR-296-5p in 293 T cells. Hdac3 inhibited miR-296-5p expression by binding to its promoter region. The effects of overexpressed Hdac3 on lymphocyte apoptosis was counterweighed via downregulation of Bcl-xl or upregulation of miR-296-5p, the mechanism of which was further validated in a rat model of DM. Taken together, the Hdac3-mediated upregulation of Bcl-xl via inhibiting miR-296-5p promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.
Highlights
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by immune-mediated destruction of pancreatic islet β-cells (Vatanen et al, 2018)
The results showed that miR-296-5p was downregulated and B-cell leukemia-XL (Bcl-xl) was upregulated in peripheral blood mononuclear cells (PBMCs) of patients with T1DM compared to healthy individuals (Figures 1B,C)
Results from Western blot analysis showed that the protein expression of B-cell leukemia-XL (BCL-XL) was significantly increased in PBMCs of patients with T1DM compared to healthy individuals (Figure 1D), suggesting the low expression of miR-296-5p and high expression of Bcl-xl in PBMCs of patients with T1DM
Summary
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder characterized by immune-mediated destruction of pancreatic islet β-cells (Vatanen et al, 2018). Patients with T1DM possess a higher risk to suffer from epilepsy compared with healthy individuals (Dafoulas et al, 2017). Coronary heart disease is the main factor responsible for the mortality of patients with T1DM that is closely related to insulin resistance (Bjornstad et al, 2018). It is of great importance to develop novel and effective therapeutic strategies for T1DM treatment. The occurrence and development of DM have been suggested to be closely correlated with histone deacetylases (HDACs; Zhang et al, 2019b). In a mouse model of DM, the inhibition of Hdac has been reported to activate NF-E2-related factor 2 to alleviate liver damage caused by DM (Zhang et al, 2018)
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