Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209.
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29209
J Immunol. 2020 Aug 15;205(4):987-993. doi: 10.4049/jimmunol.2000330. Epub 2020 Jul 20.
Long noncoding RNAs (lncRNAs) have been demonstrated to play important regulatory roles in gene expression, from histone modification to protein stability. However, the functions of most identified lncRNAs are not known. In this study, we investigated the role of an lncRNA called AW112010. The expression of AW112010 was significantly increased in CD4 T cells from C57BL/6J mice activated in vivo with myelin oligodendrocyte glycoprotein, enterotoxin B, or in vitro with anti-CD3 anti-CD28 mAbs, thereby demonstrating that activation of T cells leads to induction of AW112010. In contrast, anti-inflammatory cannabinoids such as cannabidiol or δ-9-tetrahydrocannabinol decreased the expression of AW112010 in T cells. Interestingly, the expression of AW112010 was high in in vitro-polarized Th1 and Th17 cells but low in Th2 cells, suggesting that this lncRNA may regulate inflammation. To identify genes that might be regulated by AW112010, we used chromatin isolation by RNA purification, followed by sequencing. This approach demonstrated that AW112010 regulated the transcription of IL-10. Additionally, the level of IL-10 in activated T cells was low when the expression of AW112010 was increased. Use of small interfering RNA to knock down AW112010 expression in activated T cells led to increased IL-10 expression and a decrease in the expression of IFN-γ. Further studies showed that AW112010 interacted with histone demethylase KDM5A, which led to decreased H3K4 methylation in IL-10 gene locus. Together, these studies demonstrate that lncRNA AW112010 promotes the differentiation of inflammatory T cells by suppressing IL-10 expression through histone demethylation.
长链非编码 RNA（lncRNA）已被证明在基因表达中发挥重要的调节作用，从组蛋白修饰到蛋白质稳定性。然而，大多数已鉴定的 lncRNA 的功能尚不清楚。在这项研究中，我们研究了一种称为 AW112010 的 lncRNA 的作用。在体内用髓鞘少突胶质细胞糖蛋白、肠毒素 B 或体外用抗 CD3 抗 CD28 mAb 激活的 C57BL/6J 小鼠的 CD4 T 细胞中，AW112010 的表达显著增加，从而表明 T 细胞的激活导致 AW112010 的诱导。相比之下，抗炎大麻素，如大麻二酚或 δ-9-四氢大麻酚，降低了 T 细胞中 AW112010 的表达。有趣的是，AW112010 在体外极化的 Th1 和 Th17 细胞中表达较高，而在 Th2 细胞中表达较低，表明这种 lncRNA 可能调节炎症。为了鉴定可能受 AW112010 调节的基因，我们使用 RNA 纯化的染色质分离，然后进行测序。这种方法表明，AW112010 调节了 IL-10 的转录。此外，当 AW112010 的表达增加时，激活的 T 细胞中的 IL-10 水平较低。用小干扰 RNA 敲低激活的 T 细胞中的 AW112010 表达会导致 IL-10 表达增加和 IFN-γ 表达减少。进一步的研究表明，AW112010 与组蛋白去甲基化酶 KDM5A 相互作用，导致 IL-10 基因座的 H3K4 甲基化减少。总之，这些研究表明，lncRNA AW112010 通过组蛋白去甲基化抑制 IL-10 表达，促进炎症性 T 细胞的分化。
