Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells

In vitro induced human regulatory T cells (iTregs) have in vivo therapeutic utility. MicroRNAs (miRNAs) are a family of approximately 22-nucleotide non-coding RNAs that are processed from longer precursors by the RNases Drosha and Dicer. miRNAs regulate post-transcriptional protein expression through messenger RNA destabilization or translational silencing; miR-142-3p regulates natural Treg function through autophagy. We hypothesized that this miRNA may also have an iTreg regulation function. Antagomir-mediated knockdown of miR-142-3p improved Foxp3 (forkhead box P3) expression, regulatory function, cytokine expression, and apoptosis of iTregs in vitro, with or without inflammatory cytokine stimulation. miR-142-3p knockdown increased autophagy-related protein 16-1-mediated autophagy. Target prediction and luciferase assay results indicated that miR-142-3p binds directly to lysine demethylase 6A (KDM6A), which resulted in demethylation of H3K27me3 and in turn upregulated expression of the anti-apoptotic protein Bcl-2. Based on these results, we propose a novel strategy that uses knockdown of miR-142-3p to enhance anti-apoptotic ability and function of iTregs by increasing KDM6A and Bcl-2 expression. This approach might be used as a treatment to control established chronic immune-mediated autoimmune and inflammatory diseases.