29 m⁶A-RNA Methylation (Epitranscriptomic) Regulators Are Regulated in 41 Diseases including Atherosclerosis and...

We performed a database mining on 102 transcriptomic datasets for the expressions of 29 m⁶A-RNA methylation (epitranscriptomic) regulators (m⁶A-RMRs) in 41 diseases and cancers and made significant findings: (1) a few m⁶A-RMRs were upregulated; and most m⁶A-RMRs were downregulated in sepsis, acute respiratory distress syndrome, shock, and trauma; (2) half of 29 m⁶A-RMRs were downregulated in atherosclerosis; (3) inflammatory bowel disease and rheumatoid arthritis modulated m⁶A-RMRs more than lupus and psoriasis; (4) some organ failures shared eight upregulated m⁶A-RMRs; end-stage renal failure (ESRF) downregulated 85% of m⁶A-RMRs; (5) Middle-East respiratory syndrome coronavirus infections modulated m⁶A-RMRs the most among viral infections; (6) proinflammatory oxPAPC modulated m⁶A-RMRs more than DAMP stimulation including LPS and oxLDL; (7) upregulated m⁶A-RMRs were more than downregulated m⁶A-RMRs in cancer types; five types of cancers upregulated ≥10 m⁶A-RMRs; (8) proinflammatory M1 macrophages upregulated seven m⁶A-RMRs; (9) 86% of m⁶A-RMRs were differentially expressed in the six clusters of CD4⁺Foxp3⁺ immunosuppressive Treg, and 8 out of 12 Treg signatures regulated m⁶A-RMRs; (10) immune checkpoint receptors TIM3, TIGIT, PD-L2, and CTLA4 modulated m⁶A-RMRs, and inhibition of CD40 upregulated m⁶A-RMRs; (11) cytokines and interferons modulated m⁶A-RMRs; (12) NF-κB and JAK/STAT pathways upregulated more than downregulated m⁶A-RMRs whereas TP53, PTEN, and APC did the opposite; (13) methionine-homocysteine-methyl cycle enzyme Mthfd1 downregulated more than upregulated m⁶A-RMRs; (14) m⁶A writer RBM15 and one m⁶A eraser FTO, H3K4 methyltransferase MLL1, and DNA methyltransferase, DNMT1, regulated m⁶A-RMRs; and (15) 40 out of 165 ROS regulators were modulated by m⁶A eraser FTO and two m⁶A writers METTL3 and WTAP. Our findings shed new light on the functions of upregulated m⁶A-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.