Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells
Blockade of miR-142-3p promotes anti-apoptotic and suppressive function by inducing KDM6A-mediated H3K27me3 demethylation in induced regulatory T cells
复制标题
阻断 miR-142-3p 通过诱导诱导调节性 T 细胞中 KDM6A 介导的 H3K27me3 去甲基化来促进抗凋亡和抑制功能
DOI：
10.1038/s41419-019-1565-6
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发表时间：
2019-04-15
影响因子：
9
通讯作者：
Wang, Xuehao
中科院分区：
文献类型：
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作者：
Gao, Ji;Cu, Jian;Wang, Xuehao
体外诱导的人调节性T细胞（iTreg）具有体内治疗效用。微小RNA（miRNAs）是由约22个核苷酸的非编码RNA组成的家族，其由RNA酶Drosha和Dicer从较长的前体加工而成。miRNA通过信使RNA去稳定化或翻译沉默调节转录后蛋白表达; miR-142- 3 p通过自噬调节天然Treg功能。我们推测该miRNA可能也具有iTreg调节功能。在有或没有炎性细胞因子刺激的情况下，antagomir介导的miR-142- 3 p敲低在体外改善了Foxp 3（叉头框P3）表达、调节功能、细胞因子表达和iT细胞凋亡。miR-142- 3 p敲低增加了自噬相关蛋白16-1介导的自噬。靶点预测和荧光素酶检测结果表明，miR-142- 3 p直接与赖氨酸脱甲基酶6A（KDM 6A）结合，导致H3 K27 me 3脱甲基，进而上调抗凋亡蛋白Bcl-2的表达。基于这些结果，我们提出了一种新的策略，即通过敲低miR-142- 3 p来增加KDM 6A和Bcl-2的表达，从而增强iT细胞的抗凋亡能力和功能。这种方法可能被用作控制已建立的慢性免疫介导的自身免疫性和炎症性疾病的治疗。
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.