AUTHOR=Hu Qibo , Che Guanghua , Yang Yu , Xie Hongchang , Tian Jing 

TITLE=Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p/Bcl-xl Axis

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.536854

DOI=10.3389/fgene.2020.536854

ISSN=1664-8021

ABSTRACT=<p>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 <italic>Hdac3</italic> on T1DM progression. The expression of <italic>miR-296-5p</italic> 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 <italic>miR-296-5p</italic> and <italic>Bcl-xl</italic> was verified by using dual-luciferase reporter gene assay, and the binding between <italic>Hdac3</italic> and the promoter region of <italic>miR-296-5p</italic> was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. <italic>miR-296-5p</italic> expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between <italic>miR-296-5p</italic> and <italic>Bcl-xl</italic> in mouse TE15 B lymphocytes. <italic>Bcl-xl</italic> was further validated to be targeted and negatively regulated by <italic>miR-296-5p</italic> in 293 T cells. <italic>Hdac3</italic> inhibited <italic>miR-296-5p</italic> expression by binding to its promoter region. The effects of overexpressed <italic>Hdac3</italic> on lymphocyte apoptosis was counterweighed <italic>via</italic> downregulation of <italic>Bcl-xl</italic> or upregulation of <italic>miR-296-5p</italic>, the mechanism of which was further validated in a rat model of DM. Taken together, the <italic>Hdac3</italic>-mediated upregulation of <italic>Bcl-xl via</italic> inhibiting <italic>miR-296-5p</italic> promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.</p>