Gene Expression Profile Of RNA Demethylases And RNA Methyltransferases

There are chemical modifications on DNA,RNA,and proteins,among which the chemical modification of RNA is the most abundant.N6-methyladenosine(m~6A)is the most common and abundant methylation modification in eukaryotic m RNA and long-chain non-coding RNA.Methyltransferase and demethylase co-regulate dynamic reversible RNA modifications.RNA demethylases are a class of Fe(II)and 2-oxoglutarate(2OG)dependent enzymes that have different single-stranded nucleic acid substrate selectivity.Nucleoside methyltransferase(MTase)is a diverse protein family,which is characterized by the presence of methyltransferases like domains and conserved S-adenosylmethionine(SAM)binding domains formed by the central seven-stranded beta-sheet structure.We summarized that only four enzymes were identified with demethylation activity for human RNA through information collection.These enzymes,including ALKHB5,FTO,ALKBH3,and ALKBH1.We also summarized that only METTL3,METTL14,METTL2,METTL16,METTL8,METTL6,TRMT6,and TRMT61A were identified whose methylation products are RNA demethylases'substrates through information collection.However,a comprehensive analysis of the gene expression profiles of such enzymes has not been performed to classify them according to evolutionary criteria and to guide the functional prediction.Here,we conducted extensive searches of databases to collect all members of previously identified RNA demethylases and methyltransferases.And based on the evolutionary analysis,gene expression level,and sequence alignment of the enzymes obtained from some databases,the gene expression profile of RNA demethylase and methyltransferase was studied through bioinformatics.To understand the origin of these enzymes in detail,we summarized the species without demethylase orthologues and methyltransferase orthologues together with the corresponding discussion of the gene sequences and structure to verify the evolution of RNA methylation and demethylation modifications.Moreover,expression and localization of RNA demethylases and methyltransferases across tissues and cells better indicate the specificity of gene expression.The clustering analysis of RNA demethylases and methyltransferases expression profiles reveals their tissue and cell specificities.To find out the relationship between survival time and gene expression in various tumors,we used AIPu Fu to draw a specific survival curve online.According to the kinds and substrates of RNA demethylase,it can be concluded that only m~6A,m~3C,and m~1A are dynamic reversible methylation modifications in RNAs.Our analysis showed that in the representative species the RNA modifications of fungi and invertebrates are very incomplete.During the period of Ciona savignyi,the m~6A methylation and demethylation modification system has been initially evolved.The Petromyzon marinus as the intermediate species in the evolution of invertebrates to fish have evolved a relatively complete system of m~6A methylation and demethylation in RNA.And m~3C methylation modification in t RNA may exist in all invertebrates and vertebrates,the m RNA m~3C methylation modification began to appear in Callorhinchus milii.From the distribution of m~3C demethylases,m~3C demethylation in RNA may also exist in all invertebrates and vertebrates.The extensive presence of TRMT6,TRMT61A,and ALKBH1 in early invertebrates and vertebrates suggest that the dynamic modification of m~1A is earlier than that of m~6A in RNA.The base modification behavior mediated by RNA demethylases and methyltransferases evolved from invertebrates,and the active sites of RNA demethylases were highly conserved during the evolution from invertebrates to humans.The highly conserved active residues of RNA methyltransferases indicate that different species have the same functional domains of RNA methyltransferases and methylation modification in the process of species evolution is also conservative.And human Alk B homolog 5(ALKBH5)of RNA demethylases has tissue specificity in skeletal muscle based on RNA expression analysis in tissues.m~5C methyltransferases NSUN4 and NSUN7 are tissue enhanced in testis,NSUN6 is tissue enhanced in the liver.RNA demethylases and methyltransferases have low tissue and cell specificity.The survival analysis of RNA demethylases confirmed that the gene expression levels were significantly correlated with the survival time of several cancers.The results provide a further understanding of the evolutionary profile of RNA modification and valuable insights into their functions.