Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA 19140, USA.
Department of Cell Biology and Genetics, School of Basic Medical Science, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
J Immunol Res. 2022 Feb 15;2022:1433323. doi: 10.1155/2022/1433323. eCollection 2022.
We performed a database mining on 102 transcriptomic datasets for the expressions of 29 mA-RNA methylation (epitranscriptomic) regulators (mA-RMRs) in 41 diseases and cancers and made significant findings: (1) a few mA-RMRs were upregulated; and most mA-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 mA-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated mA-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated mA-RMRs; end-stage renal failure (ESRF) downregulated 85% of mA-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated mA-RMRs the most among viral infections; (6) proinflammatory oxPAPC modulated mA-RMRs more than DAMP stimulation including LPS and oxLDL; (7) upregulated mA-RMRs were more than downregulated mA-RMRs in cancer types; five types of cancers upregulated ≥10 mA-RMRs; (8) proinflammatory M1 macrophages upregulated seven mA-RMRs; (9) 86% of mA-RMRs were differentially expressed in the six clusters of CD4Foxp3 immunosuppressive Treg, and 8 out of 12 Treg signatures regulated mA-RMRs; (10) immune checkpoint receptors TIM3, TIGIT, PD-L2, and CTLA4 modulated mA-RMRs, and inhibition of CD40 upregulated mA-RMRs; (11) cytokines and interferons modulated mA-RMRs; (12) NF-B and JAK/STAT pathways upregulated more than downregulated mA-RMRs whereas TP53, PTEN, and APC did the opposite; (13) methionine-homocysteine-methyl cycle enzyme Mthfd1 downregulated more than upregulated mA-RMRs; (14) mA writer RBM15 and one mA eraser FTO, H3K4 methyltransferase MLL1, and DNA methyltransferase, DNMT1, regulated mA-RMRs; and (15) 40 out of 165 ROS regulators were modulated by mA eraser FTO and two mA writers METTL3 and WTAP. Our findings shed new light on the functions of upregulated mA-RMRs in 41 diseases and cancers, nine cellular and molecular mechanisms, novel therapeutic targets for inflammatory disorders, metabolic cardiovascular diseases, autoimmune diseases, organ failures, and cancers.
我们对 102 个转录组数据集进行了数据库挖掘，以研究 41 种疾病和癌症中 29 种 mA-RNA 甲基化（表观转录组）调节剂（mA-RMRs）的表达情况，并得出了重要发现：（1）少数 mA-RMRs 上调；而大多数 mA-RMRs 在败血症、急性呼吸窘迫综合征、休克和创伤中下调；（2）动脉粥样硬化中下调了一半的 29 种 mA-RMRs；（3）炎症性肠病和类风湿关节炎比狼疮和银屑病调节更多的 mA-RMRs；（4）一些器官衰竭共同存在八种上调的 mA-RMRs；终末期肾衰竭（ESRF）下调了 85%的 mA-RMRs；（5）中东呼吸综合征冠状病毒感染在病毒感染中最能调节 mA-RMRs；（6）促炎 oxPAPC 比包括 LPS 和 oxLDL 在内的 DAMPs 刺激更能调节 mA-RMRs；（7）癌症类型中上调的 mA-RMRs 多于下调的 mA-RMRs；五种类型的癌症上调了≥10 种 mA-RMRs；（8）促炎 M1 巨噬细胞上调了七种 mA-RMRs；（9）在 CD4Foxp3 免疫抑制性 Treg 的六个聚类中，有 86%的 mA-RMRs 存在差异表达，其中 12 个 Treg 特征中有 8 个调节了 mA-RMRs；（10）免疫检查点受体 TIM3、TIGIT、PD-L2 和 CTLA4 调节 mA-RMRs，而抑制 CD40 则上调 mA-RMRs；（11）细胞因子和干扰素调节 mA-RMRs；（12）NF-B 和 JAK/STAT 通路上调的 mA-RMRs多于下调的 mA-RMRs，而 TP53、PTEN 和 APC 则相反；（13）蛋氨酸-同型半胱氨酸-甲基循环酶 Mthfd1 下调的 mA-RMRs多于上调的 mA-RMRs；（14）mA 书写器 RBM15 和一个 mA 橡皮擦 FTO、H3K4 甲基转移酶 MLL1 和 DNA 甲基转移酶 DNMT1 调节 mA-RMRs；（15）在 165 种 ROS 调节剂中，有 40 种受到 mA 橡皮擦 FTO 和两个 mA 书写器 METTL3 和 WTAP 的调节。我们的研究结果为上调的 mA-RMRs 在 41 种疾病和癌症中的功能、九个细胞和分子机制、炎症性疾病、代谢性心血管疾病、自身免疫性疾病、器官衰竭和癌症的新治疗靶点提供了新的见解。
