Negi Vinny, Paul Deepanjan, Das Sudipta, Bajpai Prashant, Singh Suchita, Mukhopadhyay Arijit, Agrawal Anurag, Ghosh Balaram
Molecular Immunogenetics Laboratory and Centre of Excellence for Translational Research in Asthma & Lung disease, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India Academy of Scientific & Innovative Research, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India.
Academy of Scientific & Innovative Research, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India Genomics & Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Delhi 110007, India.
Nucleic Acids Res. 2015 Sep 18;43(16):8057-65. doi: 10.1093/nar/gkv752. Epub 2015 Jul 23.
RNA editing of miRNAs, especially in the seed region, adds another layer to miRNA mediated gene regulation which can modify its targets, altering cellular signaling involved in important processes such as differentiation. In this study, we have explored the role of miRNA editing in CD4(+) T cell differentiation. CD4(+) T cells are an integral component of the adaptive immune system. Naïve CD4(+) T cells, on encountering an antigen, get differentiated either into inflammatory subtypes like Th1, Th2 or Th17, or into immunosuppressive subtype Treg, depending on the cytokine milieu. We found C-to-U editing at fifth position of mature miR-100, specifically in Treg. The C-to-U editing of miR-100 is functionally associated with at least one biologically relevant target change, from MTOR to SMAD2. Treg cell polarization by TGFβ1 was reduced by both edited and unedited miR-100 mimics, but percentage of Treg in PBMCs was only reduced by edited miR-100 mimics, suggesting a model in which de-repression of MTOR due to loss of unedited mir-100, promotes tolerogenic signaling, while gain of edited miR-100 represses SMAD2, thereby limiting the Treg. Such delicately counterbalanced systems are a hallmark of immune plasticity and we propose that miR-100 editing is a novel mechanism toward this end.
微小RNA（miRNA）的RNA编辑，尤其是在种子区域的编辑，为miRNA介导的基因调控增加了另一层面，这可以修饰其靶标，改变参与分化等重要过程的细胞信号传导。在本研究中，我们探索了miRNA编辑在CD4(+) T细胞分化中的作用。CD4(+) T细胞是适应性免疫系统的一个组成部分。幼稚CD4(+) T细胞遇到抗原后，根据细胞因子环境，会分化为炎症亚型如Th1、Th2或Th17，或免疫抑制亚型调节性T细胞（Treg）。我们发现成熟miR-100的第五位存在C到U的编辑，特别是在Treg中。miR-100的C到U编辑在功能上与至少一个生物学相关的靶标变化相关，从雷帕霉素靶蛋白（MTOR）到SMAD2。编辑和未编辑的miR-100模拟物都降低了转化生长因子β1（TGFβ1）诱导的Treg细胞极化，但只有编辑后的miR-100模拟物降低了外周血单核细胞（PBMC）中Treg的百分比，这表明一种模型，即由于未编辑的mir-100缺失导致MTOR的去抑制促进了耐受性信号传导，而编辑后的miR-100的增加抑制了SMAD2，从而限制了Treg。这种微妙的平衡系统是免疫可塑性的一个标志，我们提出miR-100编辑是实现这一目的的一种新机制。
