Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells
| Autor: | Yongxiang Xia, Ling Lu, Xuehao Wang, Ji Gao, Jian Gu, Zheng Ju, Shaopeng Zhang, Xiongxiong Pan, Xiaojie Gan |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Immunology Autophagy-Related Proteins Graft vs Host Disease Apoptosis Kaplan-Meier Estimate T-Lymphocytes Regulatory Article Histones Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine microRNA Autophagy Animals Humans Gene silencing lcsh:QH573-671 Drosha Cell Proliferation Histone Demethylases Mice Knockout Messenger RNA Gene knockdown biology Chemistry lcsh:Cytology Antagomirs FOXP3 Forkhead Transcription Factors Cell Biology Demethylation Up-Regulation Cell biology MicroRNAs 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 030220 oncology & carcinogenesis biology.protein Cytokines Dicer |
| Zdroj: | Cell Death and Disease, Vol 10, Iss 5, Pp 1-13 (2019) Cell Death & Disease |
| ISSN: | 2041-4889 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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