isomiRs–Hidden Soldiers in the miRNA Regulatory Army, and How to Find Them?

Glogovitis, Ilias; Yahubyan, Galina; Würdinger, Thomas; Koppers-Lalić, Danijela; Baev, Vesselin

doi:10.3390/biom11010041

Cited by 18 publications

(19 citation statements)

References 131 publications

(126 reference statements)

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“…It is mediated by the adenosine deaminases ADARs, principally ADAR1/2 [ 67 , 68 ]. A-to-I change can occur in the processing of pri-miRNA and pre-miRNA; if within the seed sequence, given the identification of I as G, RNA editing can affect the role of the modified molecules, resulting for example in the regulation of new target genes [ 69 , 70 ].…”

Section: Biogenesis Of Isomirsmentioning

confidence: 99%

Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Zelli

Compagnoni

Capelli

et al. 2021

Genes

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The advent of Next Generation Sequencing technologies brought with it the discovery of several microRNA (miRNA) variants of heterogeneous lengths and/or sequences. Initially ascribed to sequencing errors/artifacts, these isoforms, named isomiRs, are now considered non-canonical variants that originate from physiological processes affecting the canonical miRNA biogenesis. To date, accurate IsomiRs abundance, biological activity, and functions are not completely understood; however, the study of isomiR biology is an area of great interest due to their high frequency in the human miRNome, their putative functions in cooperating with the canonical miRNAs, and potential for exhibiting novel functional roles. The discovery of isomiRs highlighted the complexity of the small RNA transcriptional landscape in several diseases, including cancer. In this field, the study of isomiRs could provide further insights into the miRNA biology and its implication in oncogenesis, possibly providing putative new cancer diagnostic, prognostic, and predictive biomarkers as well. In this review, a comprehensive overview of the state of research on isomiRs in different cancer types, including the most common tumors such as breast cancer, colorectal cancer, melanoma, and prostate cancer, as well as in the less frequent tumors, as for example brain tumors and hematological malignancies, will be summarized and discussed.

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Section: Biogenesis Of Isomirsmentioning

confidence: 99%

Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Zelli

Compagnoni

Capelli

et al. 2021

Genes

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“…Recently, we have reviewed currently available computational tools for isomiRs analysis [ 13 ]. Most of the tools emphasize the isomiR identification but failed to extend the analysis further, exploring the DE of individual isomiR species across samples and thus providing the means for novel biomarker discovery.…”

Section: Introductionmentioning

confidence: 99%

miRGalaxy: Galaxy-Based Framework for Interactive Analysis of microRNA and isomiR Sequencing Data

Glogovitis

Yahubyan²,

Würdinger

et al. 2021

Cancers

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Tools for microRNA (miR) sequencing data analyses are broadly used in biomedical research. However, the complexity of computational approaches still remains a challenge for biologists with scarce experience in data analytics and bioinformatics. Here, we present miRGalaxy, a Galaxy-based framework for comprehensive analysis of miRs and their sequence variants—miR isoforms (isomiRs). Though isomiRs are commonly reported in deep-sequencing experiments, their detailed structure complexity and specific differential expression (DE) remain not fully examined by the majority of the available analysis tools. miRGalaxy encompasses biologist-user-friendly tools and workflows dedicated to the analysis of the isomiR-ome and its complex behavior in various biological samples. miRGalaxy is developed as a modular, accessible, redistributable, shareable, and user-friendly framework for scientists working with small RNA (sRNA)-seq data. Due to its modular workflow, advanced users can customize the steps and tools for their needs. In addition, the framework provides an analysis report where the significant output results are summarized in charts and visualizations. miRGalaxy can be accessed via preconfigured Docker image flavor and a Toolshed installation if the user already has a running Galaxy instance. Over the last decade, studies on the expression of miRs and isomiRs in normal and deregulated tissues have led to the discovery of their potential as diagnostic biomarkers. The detection of miRs in biofluids further expanded the exploration of the miR repertoire as a source of liquid biopsy biomarkers. Here we show the miRGalaxy framework application for in-depth analysis of the sRNA-seq data from two different biofluids, milk and plasma, to identify, annotate, and discover specific differentially expressed miRs and isomiRs.

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“…Most of these isoforms, called isomiRs, have modifications in only one or two nucleotides compared to their reference sequences. isomiRs are generated through various mechanisms, such as alternative cleavage by Drosha/Dicer and non-templated nucleotide additions (4)(5)(6). These alternative processing mechanisms give rise to different types of modifications that can be used to categorise isomiRs (Fig 1B) (5).…”

Section: Introductionmentioning

confidence: 99%

“…These alternative processing mechanisms give rise to different types of modifications that can be used to categorise isomiRs (Fig 1B) (5). As isomiRs are an abundant, highly expressed (6)(7)(8), and very diverse group of RNA species that display distinct…”

Section: Introductionmentioning

confidence: 99%

isomiRs-specific differential expression is the rule, not the exception: Are we missing hundreds of species in microRNA analysis?

Schmauch

Laitinen

Turunen

et al. 2021

Preprint

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MicroRNAs (miRNAs) are small RNA molecules that act as regulators of gene expression through targeted mRNA degradation. They are involved in many biological and pathophysiological processes and are widely studied as potential biomarkers and therapeutics agents for human diseases, including cardiovascular disorders. Recently discovered isoforms of miRNAs (isomiRs) exist in high quantities and are very diverse. Despite having few differences with their corresponding reference miRNAs, they display specific functions and expression profiles, across tissues and conditions. However, they are still overlooked and understudied, as we lack a comprehensive view on their condition-specific regulation and impact on differential expression analysis. Here, we show that isomiRs can have major effects on differential expression analysis results, as their expression is independent of their host miRNA genes or reference sequences. We present two miRNA-seq datasets from human umbilical vein endothelial cells, and assess isomiR expression in response to senescence and compartment-specificity (nuclear/cytosolic) under hypoxia. We compare three different methods for miRNA analysis, including isomiR-specific analysis, and show that ignoring isomiRs induces major biases in differential expression. Moreover, isomiR analysis permits higher resolution of complex signal dissection, such as the impact of hypoxia on compartment localization, and differential isomiR type enrichments between compartments. Finally, we show important distribution differences across conditions, independently of global miRNA expression signals. Our results raise concerns over the quasi exclusive use of miRNA reference sequences in miRNA-seq processing and experimental assays. We hope that our work will guide future isomiR expression studies, which will correct some biases introduced by golden standard analysis, improving the resolution of such assays and the biological significance of their downstream studies.

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isomiRs–Hidden Soldiers in the miRNA Regulatory Army, and How to Find Them?

Cited by 18 publications

References 131 publications

Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

Emerging Role of isomiRs in Cancer: State of the Art and Recent Advances

miRGalaxy: Galaxy-Based Framework for Interactive Analysis of microRNA and isomiR Sequencing Data

isomiRs-specific differential expression is the rule, not the exception: Are we missing hundreds of species in microRNA analysis?

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