EpisomiR, a New Family of miRNAs, and Its Possible Roles in Human Diseases

Abstract

MicroRNAs (miRNAs) are synthesized through a canonical pathway and play a role in human diseases, such as cancers and cardiovascular, neurodegenerative, psychiatric, and chronic inflammatory diseases. The development of sequencing technologies has enabled the identification of variations in noncoding miRNAs. These miRNA variants, called isomiRs, are generated through a non-canonical pathway, by several enzymes that alter the length and sequence of miRNAs. The isomiR family is, now, expanding further to include episomiRs, which are miRNAs with different modifications. Since recent findings have shown that isomiRs reflect the cell-specific biological function of miRNAs, knowledge about episomiRs and isomiRs can, possibly, contribute to the optimization of diagnosis and therapeutic technology for precision medicine.

Keywords: RNA modification; methylation; miRNA variants.

Figure 1

Synthesis of miRNAs from the genome. Enzymes involved in the synthesis of miRNAs are: ADAR, adenosine deaminase RNA specific; AGO2, argonaute RISC catalytic component 2; DICER1, dicer 1, ribonuclease III; DGCR8, DiGeorge syndrome critical region gene 8, DGCR8 microprocessor complex subunit; DROSHA, drosha ribonuclease III; miRISC, miRNA-induced silencing complex; Nibbler Homolog, EXD3, exonuclease 3′–5′ domain containing 3; PARN, poly(A)-specific ribonuclease; RAN, a member of RAS oncogene family; TUT4, terminal uridylyltransferase 4; and TUT7, terminal uridylyltransferase 7.

Figure 2

Generation of isomiR. Enzymes affecting the length, sequence, and modifications of miRNAs are: ADAR, adenosine deaminase RNA specific; APOBEC1, apolipoprotein B mRNA editing enzyme catalytic subunit; DICER1, dicer 1, ribonuclease III; DROSHA, drosha ribonuclease III; METTL3, methyltransferase-like protein 3; MTPAR, mitochondrial poly(A) polymerase; Nibbler, exonuclease 3′–5′ domain containing 3; PAPOLG, poly(A) polymerase gamma; PARN, poly(A)-specific ribonuclease; TENT2, terminal nucleotidyltransferase 2; TUT1, terminal uridylyltransferase 1; TUT3, terminal nucleotidyltransferase 4B; TUT4, terminal uridylyltransferase 4; and TUT7, terminal uridylyltransferase 7.

Figure 3

EpisomiR, a subtype of isomiR with different miRNA methylations. Although not fully understood, the methylation of miRNAs modulates miRNA silencing function and mRNA degradation. Recently developed state-of-the-art sequencing techniques, such as tunnel current sequencing and mass spectrometry analysis, enables the detection of m6A and 5mC modifications. 5mC, 5-methylcytosine; AGO2, argonaute RISC catalytic component 2; DNMT3A, DNA methyltransferase 3 alpha; m6A, N6-methyladenosine; m7G, 7-methylguanosine; METTL1, methyltransferase-like protein 1; METTL3, methyltransferase-like protein 3; miRISC, miRNA-induced silencing complex.

Figure 4

Outlook on high-precision medical care, achieved by the profiling of isomiR. A recent study, using single-cell sequencing of various tissues, has provided links with data from liquid biopsy, such as that of peripheral blood. Given that the expression of isomiR-generating enzymes varies, according to the cell populations present in tissues, the study of isomiR will enable the detection of cell-specific expression patterns. This will improve the diagnosis of diseases, in which unique expression patterns are observed due to genomic and epigenomic variabilities, and will enable the development of precision medicine based on liquid biopsy analyses.