一种新的长非编码 RNA，lnc-RNU12，通过 c-JUN 和 CCNL2 影响类风湿关节炎中的 T 细胞周期。
A novel long non-coding RNA, lnc-RNU12, influences the T-cell cycle via c-JUN and CCNL2 in rheumatoid arthritis.
机构信息
Center for Genetic Epidemiology and Genomics, School of Public Health, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China.
Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Medical College of Soochow University, Suzhou, Jiangsu, P. R. China.
出版信息
Rheumatology (Oxford). 2023 May 2;62(5):1955-1963. doi: 10.1093/rheumatology/keac553.
OBJECTIVES
Long non-coding RNAs (lncRNAs) play important roles in RA pathogenesis. However, specific lncRNAs that regulate gene expression in RA pathogenesis are poorly known. This study was undertaken to characterize a novel lncRNA (lnc-RNU12) that has a lower-than-normal expression level in RA patients.
METHODS
We performed initial genome-wide lncRNA microarray screening in peripheral blood mononuclear cells from 28 RA cases and 18 controls. Multiple methods were used to validate the detected associations between lncRNAs and RA. Furthermore, we identified the source and characteristics of the highlighted lncRNAs, detected the target genes, and determined the functional effect on immune cells through lncRNA knock-down in Jurkat T cell lines.
RESULTS
lnc-RNU12 was downregulated in peripheral blood mononuclear cells and T cell subtypes of RA patients and was genetically associated with RA risk. lnc-RNU12 mediates the effect of microbiome alterations on RA risk. Activation of T cells caused low expression of lnc-RNU12. Knock-down of lnc-RNU12 in Jurkat T cells caused cell cycle S-phase arrest and altered the expression of protein-coding genes related to the cell cycle and apoptosis (e.g. c-JUN, CCNL2, CDK6, MYC, RNF40, PKM, VPS35, DNAJB6 and FLCN). Finally, c-JUN and CCNL2 were identified as target genes of lnc-RNU12 at the mRNA and protein expression levels. RNA-binding protein immunoprecipitation assays verified the interaction between lnc-RNU12 and the two proteins (c-Jun and cyclin L2) in Jurkat cells.
CONCLUSIONS
Our study suggested that lnc-RNU12 was involved in the pathogenesis of RA by influencing the T cell cycle by targeting c-JUN and CCNL2.
目的
长链非编码 RNA（lncRNA）在 RA 发病机制中发挥重要作用。然而，调节 RA 发病机制中基因表达的特定 lncRNA 知之甚少。本研究旨在描述一种新型 lncRNA（lnc-RNU12），其在 RA 患者中的表达水平低于正常水平。
方法
我们对 28 例 RA 病例和 18 例对照的外周血单个核细胞进行了全基因组 lncRNA 微阵列筛选。采用多种方法验证了 lncRNA 与 RA 之间的关联。此外，我们确定了高亮 lncRNA 的来源和特征，检测了靶基因，并通过 Jurkat T 细胞系中的 lncRNA 敲低确定了对免疫细胞的功能影响。
结果
lnc-RNU12 在 RA 患者的外周血单个核细胞和 T 细胞亚型中表达下调，与 RA 风险具有遗传相关性。lnc-RNU12 介导了微生物组改变对 RA 风险的影响。T 细胞的激活导致 lnc-RNU12 的低表达。Jurkat T 细胞中 lnc-RNU12 的敲低导致细胞周期 S 期停滞，并改变了与细胞周期和凋亡相关的蛋白质编码基因的表达（例如 c-JUN、CCNL2、CDK6、MYC、RNF40、PKM、VPS35、DNAJB6 和 FLCN）。最后，c-JUN 和 CCNL2 被鉴定为 lnc-RNU12 在 mRNA 和蛋白表达水平上的靶基因。RNA 结合蛋白免疫沉淀实验验证了 lnc-RNU12 在 Jurkat 细胞中与这两种蛋白（c-Jun 和 cyclin L2）的相互作用。
结论
我们的研究表明，lnc-RNU12 通过靶向 c-JUN 和 CCNL2 影响 T 细胞周期，从而参与 RA 的发病机制。
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