Li Tan, Wang Tianlong, Jing Jingjing, Sun Liping
Department of Cardiovascular Ultrasound, The First Hospital of China Medical University, Shenyang, People's Republic of China.
The First Clinical College of China Medical University, The First Hospital of China Medical University, Shenyang, People's Republic of China.
J Inflamm Res. 2021 Aug 29;14:4245-4258. doi: 10.2147/JIR.S327152. eCollection 2021.
Aberrant expression of N6-methyladenosine (m6A) RNA modification regulators plays a critical role in a variety of human diseases. However, their implication in abdominal aortic aneurysm (AAA) remains largely unknown. Herein, we sought to explore the general expression pattern and potential functions of m6A regulators in AAA.
We analyzed gene expression data of m6A regulators in human AAA and normal tissues from public GEO database. The R package and other tools such as m6A2Target database, Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses, gene set variation analysis (GSVA), Search Tool for the Retrieval of Interacting Genes (STRING), starBase, miRDB and Cytoscape software were applied for bioinformatics analysis to investigate the downstream molecular mechanisms and upstream regulatory mechanisms for distinctly expressed regulators. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) were performed to validate the expression of key m6A regulators in our collected human AAA specimens.
We found that METTL14 and HNRNPC were the downregulated m6A regulators, and RBM15B was the upregulated methylation transferase in human AAA. The modified genes were primarily enriched in RNA catabolic process, regulation of translation, focal adhesion, transcription coregulator activity, ribosome, RNA transport, cell cycle, et al. METTL14, HNRNPC and RBM15B levels were correlated with the immune infiltration degree of Tcm, macrophages, mast cells, Tgd and NK CD56bright cells. A total of 154 and 76 target genes of three regulators were separately involved in body metabolism and autophagy in AAA disease, and their interactive relationships and hub genes were identified. The lncRNA-miRNA-mRNA interaction regulatory networks were also constructed for METTL14, HNRNPC and RBM15B. Based on our clinical tissue and serum samples, METTL14 exhibited lower expression levels in AAA and its rupture type, and low METTL14 expression was associated with high levels of WBC and CRP (all < 0.05).
Our study presents an overview of the expression pattern and functional significance of m6A regulators in human AAA. Our findings will provide a valuable resource that may guide both mechanistic and therapeutic analyses about the role of key m6A regulators in AAA.
N6-甲基腺苷（m6A）RNA修饰调节因子的异常表达在多种人类疾病中起关键作用。然而，它们在腹主动脉瘤（AAA）中的作用仍 largely 未知。在此，我们试图探索m6A调节因子在AAA中的总体表达模式和潜在功能。
我们分析了来自公共GEO数据库的人类AAA和正常组织中m6A调节因子的基因表达数据。应用R包以及其他工具，如m6A2Target数据库、基因本体（GO）功能和京都基因与基因组百科全书（KEGG）通路分析、基因集变异分析（GSVA）、检索相互作用基因的搜索工具（STRING）、starBase、miRDB和Cytoscape软件进行生物信息学分析，以研究差异表达调节因子的下游分子机制和上游调节机制。进行定量实时PCR（qRT-PCR）和酶联免疫吸附测定（ELISA）以验证我们收集的人类AAA标本中关键m6A调节因子的表达。
我们发现METTL14和HNRNPC是人类AAA中下调的m6A调节因子，而RBM15B是上调的甲基转移酶。修饰的基因主要富集于RNA分解代谢过程、翻译调控、粘着斑、转录共调节因子活性、核糖体、RNA转运、细胞周期等。METTL14、HNRNPC和RBM15B的水平与Tcm、巨噬细胞、肥大细胞、Tgd和NK CD56bright细胞的免疫浸润程度相关。三个调节因子的总共154个和76个靶基因分别参与AAA疾病中的身体代谢和自噬，并确定了它们的相互作用关系和枢纽基因。还构建了METTL14、HNRNPC和RBM15B的lncRNA-miRNA-mRNA相互作用调节网络。基于我们的临床组织和血清样本，METTL14在AAA及其破裂类型中表达水平较低，并且低METTL14表达与高水平的白细胞和CRP相关（均<0.05）。
我们的研究概述了m6A调节因子在人类AAA中的表达模式和功能意义。我们的发现将提供有价值的资源，可能指导关于关键m6A调节因子在AAA中作用的机制和治疗分析。
