MiREDiBase, a manually curated database of validated and putative editing events in microRNAs

MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

A concurrent canonical and modified miRNAome pan-cancer study on TCGA and TARGET cohorts leads to an enhanced resolution in cancer

MiRNA Epitranscriptomics has placed a new layer of complexity in the cancer field. Despite miRNA editing and shifted miRNA isoforms are gaining attention due to recent improvements in next-generation sequencing, a simultaneous study of both modifications in cancer is still missing. Here, we concurrently profiled multiple miRNA modifications, such as A-to-I RNA editing and shifted miRNA isoforms, in >13K adult and pediatric tumor samples across 38 distinct cancer cohorts from The Cancer Genome Atlas and The Therapeutically Applicable Research to Generate Effective Treatments datasets. We investigated the differences among canonical miRNAs and a wider comprehensive miRNAome from the expression, clustering, dysregulation, and prognostic perspective. Interestingly, the wider miRNAome boosted clustering results, uniquely outlining cohorts' clinical-pathological features. The abundance of expressed miRNA isoforms directly related to the activation/deactivation of critical carcinogenesis pathways. We found dysregulated modified miRNAs characterized by an opposite expression trend than their canonical counterparts in cancer, potentially impacting their targetome and function. Our study emphasizes the importance of modified miRNAs as potential cancer biomarkers and gene expression regulators, outlining once more the importance of going beyond the well-established paradigm of one-mature-miRNA per miRNA arm.

Detecting and Characterizing A-To-I microRNA Editing in Cancer

Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. The employment of powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Detecting and Characterizing A-to-I MicroRNA Editing in Cancer

RNA editing involves the insertion, deletion or substitution of single nucleotides within a RNA molecule, without altering the DNA sequence. Adenosine to inosine (A-to-I) editing consists of an RNA modification where single adenosines along the RNA sequence are converted into inosines. Such a biochemical transformation is catalyzed by enzymes belonging to the family of adenosine deaminases acting on RNA (ADARs) and occurs either co- or post-transcriptionally. Initially, the A-to-I RNA editing phenomenon was discovered and studied in messenger RNAs (mRNAs), where it can influence RNA splicing and cause the recoding of codon sequences. The employment of more powerful, high-throughput detection methods has recently revealed that A-to-I editing widely occurs in non-coding RNAs, including microRNAs (miRNAs). MiRNAs are a class of small regulatory non-coding RNAs (ncRNAs) acting as translation inhibitors, known to exert relevant roles in controlling cell cycle, proliferation, and cancer development. Indeed, a growing number of recent researches have evidenced the importance of miRNA editing in cancer biology by exploiting various detection and validation methods. Herein, we briefly overview early and currently available A-to-I miRNA editing detection and validation methods and discuss the significance of A-to-I miRNA editing in human cancer.

Editing and Expression of miR-589-5p as an Important Biomarker in Colorectal Cancer

Objectives: Colorectal cancer (CRC) is recognized as the third most common cancer worldwide. Recently, emerging evidence showed that microRNA (miRNA) A-to-I editing plays crucial roles in cancer prognosis as well as cancer therapy. However, the relationship between CRC and miRNA editing remains not fully understood. Herein, we presented the first comprehensive analysis of miRNA editing events in CRC. Methods: Using patient data from The Cancer Genome Atlas (TCGA), we performed editing events and detected the expression levels of miR-589-5p. Results: we identified both editing events and the expression levels of miR-589-5p are significantly associated with Consensus Molecular Subtyping (CMS), especially for CMS4. The editing and expression levels of miR-589-5p impact almost completely different sets of gene expression, indicating the edited miR-589-5p plays a different role in CRC progression, compared to the wildtype miR-589-5p. Conclusions: In conclusion, our study provided the first association of miRNA editing and CRC. We demonstrated that expression and editing level of miR‑589‑5p may work as a novel biomarker for both prognosis and diagnosis in CRC.

MiREDiBase: a manually curated database of validated and putative editing events in microRNAs

MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

Characterizing relevant microRNA editing sites in Parkinson’s disease

MicroRNAs (miRNAs) are extensively edited in human brains. However, the functional relevance of miRNA editome is largely unknown in Parkinson’s disease (PD). By analyzed small RNA sequencing profiles of brain tissues of 43 PD patients and 88 normal controls, we totally identified 421 miRNA editing sites with significantly different editing levels in prefrontal cortices of PD patients (PD-PC). A-to-I edited miR-497-5p has significantly higher expression levels in PD-PC compared to normal controls and directly represses OPA1 and VAPB, which potentially contributes to the progressive neurodegeneration of PD patients. These results provide new insights into mechanistic understanding, novel diagnostic and therapeutic clues of PD.

Deciphering miRNAs’ Action through miRNA Editing

MicroRNAs (miRNAs) are small non-coding RNAs with the capability of modulating gene expression at the post-transcriptional level either by inhibiting messenger RNA (mRNA) translation or by promoting mRNA degradation. The outcome of a myriad of physiological processes and pathologies, including cancer, cardiovascular and metabolic diseases, relies highly on miRNAs. However, deciphering the precise roles of specific miRNAs in these pathophysiological contexts is challenging due to the high levels of complexity of their actions. Indeed, regulation of mRNA expression by miRNAs is frequently cell/organ specific; highly dependent on the stress and metabolic status of the organism; and often poorly correlated with miRNA expression levels. Such biological features of miRNAs suggest that various regulatory mechanisms control not only their expression, but also their activity and/or bioavailability. Several mechanisms have been described to modulate miRNA action, including genetic polymorphisms, methylation of miRNA promoters, asymmetric miRNA strand selection, interactions with RNA-binding proteins (RBPs) or other coding/non-coding RNAs. Moreover, nucleotide modifications (A-to-I or C-to-U) within the miRNA sequences at different stages of their maturation are also critical for their functionality. This regulatory mechanism called “RNA editing” involves specific enzymes of the adenosine/cytidine deaminase family, which trigger single nucleotide changes in primary miRNAs. These nucleotide modifications greatly influence a miRNA’s stability, maturation and activity by changing its specificity towards target mRNAs. Understanding how editing events impact miRNA’s ability to regulate stress responses in cells and organs, or the development of specific pathologies, e.g., metabolic diseases or cancer, should not only deepen our knowledge of molecular mechanisms underlying complex diseases, but can also facilitate the design of new therapeutic approaches based on miRNA targeting. Herein, we will discuss the current knowledge on miRNA editing and how this mechanism regulates miRNA biogenesis and activity.

miRmedon: confident detection of microRNA editing

SummarymicroRNA (miRNA), key regulators of gene expression, are prime targets for adenosine deaminase acting on RNA (ADAR) enzymes. Although ADAR-mediated A-to-I miRNA editing has been shown to be essential for orchestrating complex processes, including neurodevelopment and cancer progression, only a few human miRNA editing sites have been reported. Several computational approaches have been developed for the detection of miRNA editing in small RNAseq data, all based on the identification of systematic mismatches of ‘G’ at primary adenosine sites in known miRNA sequences. However, these methods have several limitations, including their ability to detect only one editing site per sequence (although editing of multiple sites per miRNA has been reproducibly validated), their focus on uniquely mapping reads (although 20% of human miRNA are transcribed from multiple loci), and their inability to detect editing in miRNA genes harboring genomic variants (although 73% of human miRNA loci include a reported SNP or indel). To overcome these limitations, we developed miRmedon, that leverages large scale human variation data, a combination of local and global alignments, and a comparison of the inferred editing and error distributions, for a confident detection of miRNA editing in small RNAseq data. We demonstrate its improved performance as compared to currently available methods and describe its advantages.Availability and implementationPython source code is available at https://github.com/Amitai88/[email protected]

Identifying microRNAs and Their Editing Sites in Macaca mulatta

MicroRNAs (miRNAs) are small non-coding RNAs that are critical in post-transcriptional regulation. Macaca mulatta is an important nonhuman primate that is often used in basic and translational researches. However, the annotation of miRNAs in Macaca mulatta is far from complete, and there are no reports of miRNA editing events in Macaca mulatta, although editing may affect the biogenesis or functions of the miRNAs. To improve miRNA annotation and to reveal editing events of miRNAs in Macaca mulatta, we generated 12 small RNA profiles from eight tissues and performed comprehensive analysis of these profiles. We identified 479 conserved pre-miRNAs that have not been reported in Macaca mulatta and 17 species specific miRNAs. Furthermore, we identified 3386 editing sites with significant editing levels from 471 pre-miRNAs after analyzing the 12 self-generated and 58 additional published sRNA-seq profiles from 17 different types of organs or tissues. In addition to 16 conserved A-to-I editing sites, we identified five conserved C-to-U editing sites in miRNAs of Macaca mulatta and Homo sapiens. We also identified 11 SNPs in the miRNAs of Macaca mulatta. The analysis of the potential targets of 69 miRNAs with editing or mutation events in their seed regions suggest that these editing or mutation events severely changed their targets and their potential functions. These results significantly increase our understanding of miRNAs and their mutation/editing events in Macaca mulatta.