Long Non-Coding RNAs Target Pathogenetically Relevant Genes and Pathways in Rheumatoid Arthritis
Long Non-Coding RNAs Target Pathogenetically Relevant Genes and Pathways in Rheumatoid Arthritis
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DOI：
10.3390/cells8080816
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发表时间：
2019-08-01
期刊：
影响因子：
6
通讯作者：
Lunardi, Claudio
中科院分区：
文献类型：
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作者：
Dolcino, Marzia;Tinazzi, Elisa;Lunardi, Claudio
类风湿性关节炎（RA）是一种由遗传、环境和表观遗传因素驱动的慢性炎症性自身免疫性疾病。长链非编码RNA（LncRNA）是表观遗传机制的关键组成部分，并且已知参与自身免疫性疾病的发展。在这项工作中，我们的目的是确定显着差异表达的LncRNA（DE-LncRNA），在功能上连接到与RA严格相关的调制基因。使用Clariom D阵列，在来自4名治疗前患有早发性RA的患者和4名健康供体的外周血单核细胞（PBMC）中总共分析了542，500个转录物。结果证实了20例患者和20名对照的实时PCR。六种DE-LncRNA靶向实验验证的能够调节RA中差异表达基因（DEG）的miRNA;其中，仅FTX、HNRNPU-AS 1和RP 11 -498C9.15靶向大量DEG。最重要的是，RP 11 -498C9.15靶向了最大数量的信号传导途径，这些信号传导途径被发现被RA-DEG的全球量富集，并且已经与RA和RA滑膜细胞相关。此外，RP 11 -498C9.15靶向RA相互作用组中最高度连接的基因，从而表明其参与关键基因调控。这些结果表明，通过调节microRNA和基因表达，RP 11 -498C9.15可能在RA发病机制中发挥关键作用。
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease driven by genetic, environmental and epigenetic factors. Long non-coding RNAs (LncRNAs) are a key component of the epigenetic mechanisms and are known to be involved in the development of autoimmune diseases. In this work we aimed to identify significantly differentially expressed LncRNAs (DE-LncRNAs) that are functionally connected to modulated genes strictly associated with RA. In total, 542,500 transcripts have been profiled in peripheral blood mononuclear cells (PBMCs) from four patients with early onset RA prior any treatment and four healthy donors using Clariom D arrays. Results were confirmed by real-time PCR in 20 patients and 20 controls. Six DE-LncRNAs target experimentally validated miRNAs able to regulate differentially expressed genes (DEGs) in RA; among them, only FTX, HNRNPU-AS1 and RP11-498C9.15 targeted a large number of DEGs. Most importantly, RP11-498C9.15 targeted the largest number of signalling pathways that were found to be enriched by the global amount of RA-DEGs and that have already been associated with RA and RA-synoviocytes. Moreover, RP11-498C9.15 targeted the most highly connected genes in the RA interactome, thus suggesting its involvement in crucial gene regulation. These results indicate that, by modulating both microRNAs and gene expression, RP11-498C9.15 may play a pivotal role in RA pathogenesis.