A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme

Paul, Deepanjan; Sinha, Ashis Narayan; A, Ray; Lal, Megha; Nayak, Subhashree; Sharma, Anchal; Mehani, Bharati; Mukherjee, Debasish; Laddha, Saurabh V.; Suri, Ashish; Sarkar, Chitra; Mukhopadhyay, Arijit

doi:10.1038/s41598-017-02397-6

Cited by 61 publications

(42 citation statements)

References 55 publications

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“…Like ADAR1, ADAR2 also can modulate microRNA processing. Since a number of micro RNAs like miR-1, miR-423 are associated with heart disease we thought of investigating the microRNA profile in ADAR2 knock out mouse heart (40). Surprisingly, we did not observe any up-regulated micro RNAs in the ADAR2 -/- mice heart.…”

Section: Discussionmentioning

confidence: 99%

Modulation of ADARs mRNA expression in congenital heart defect patients

Altaf

Vesely

et al. 2018

Preprint

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27Adenosine (A) to inosine (I) RNA editing, is a hydrolytic deamination reaction catalyzed by 28 adenosine deaminase (ADAR) acting on RNA enzymes. RNA editing is a molecular process that 29 involves the post-transcriptional modification of RNA transcripts. Interestingly, few studies have 30 been carried out to determine the role of RNA editing in vascular disease. The current study 31 found that in blood samples positive for congenital heart disease (CHD) ADAR1 and ADAR2 32 expression change at RNA level was opposite to each other. That is, an increase of ADAR1 33 mRNA was noticed in human CHD cases, whereas ADAR2 mRNA was vastly down-regulated. 34The increase in ADAR1 may be explained by the stress induced by CHD. The dramatic decrease 35 in ADAR2 in CHD cases was unexpected and prompted further investigation into its effects on 36 the heart. Therefore we performed expression analysis on a microarray data encompassing 37 ischemic and non-Ischemic cardiomyopathy patient myocardial tissues. A strong down-38 regulation of ADAR2 was observed in both ischemic and especially non-ischemic cases. 39However, ADAR1 showed a mild increase in the case of non-ischemic myocardial tissues. To 40 further explore the role of ADAR2 with respect to heart physiology. We selected a protein 41 coding gene filamin B (FLNB). FLNB is known to play an important role in heart development. 42Although there were no observable changes in its expression, the editing levels of FLNB 43 dropped dramatically in ADAR2 -/mice. We also performed miRNA profiling from ADAR2 -/-44 mice heart tissue revealed a decrease in expression of miRNAs. It is established that aberrant 45 expression of these miRNAs is often associated with cardiac defects. This study proposes that 46 sufficient amounts of ADAR2 might play a vital role in preventing cardiovascular defects. 47 48 KEYWORDS 49

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Section: Discussionmentioning

confidence: 99%

Modulation of ADARs mRNA expression in congenital heart defect patients

Altaf

Vesely

et al. 2018

Preprint

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“…Based on their secondary structure, A-to-I editing could occur in pri-, pre-and mature miRNAs, although the probability of editing events is likely dependent on the lengths of these different molecules [38,42,43] (Figure 3a). RNA cis-elements and the recruited ADAR isoform might also be important for miRNA editing, as highlighted by several studies, suggesting a preferred editing activity of nuclear ADARs, i.e., ADAR2 and ADAR1p110, depending on miRNA sequence characteristics [38].…”

Section: Adarmentioning

confidence: 99%

Deciphering miRNAs’ Action through miRNA Editing

Sousa

Gjorgjieva

Dolicka

et al. 2019

IJMS

629

343

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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.

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“…Consistent with the potential function of the hsa-miR-411 mutation in GBM, miR-411-5p is considered a brain-enriched miRNA and was previously associated with neurological and neuropsychiatric disorders 89,90 . Interestingly, miR-411-5p is posttranscriptionally modified (substitution A>I (inosine) in the 5th position of miR-411-5p seed) in both normal brain and glioblastoma multiforme tissues 87,91 . The precise function of this modification is not known; however, in vitro analyses revealed that pri-miRNA editing is likely to interfere with miRNA processing 92 .…”

Section: Hsa-mir-411mentioning

confidence: 99%

Pan-Cancer analysis of somatic mutations in miRNA genes

Urbanek-Trzeciak

Galka-Marciniak

Nawrocka

et al. 2020

Preprint

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175)miRNAs are considered important players in oncogenesis, serving either as oncomiRs or suppressormiRs. Although the accumulation of somatic alterations is an intrinsic aspect of cancer development and many important cancer-driving mutations have been identified in protein-coding genes, the area of functional somatic mutations in miRNA genes is heavily understudied. Here, based on analysis of the whole-exome sequencing of over 10,000 cancer/normal sample pairs deposited within the TCGA repository, we identified and characterized over 10,000 somatic mutations in miRNA genes and showed that some of the genes are overmutated in Pan-Cancer and/or specific cancers. Nonrandom occurrence of the identified mutations was confirmed by a strong association of overmutated miRNA genes with KEGG pathways, most of which were related to specific cancer types or cancer-related processes. Additionally, we showed that mutations in some of the overmutated genes correlate with miRNA expression, cancer staging, and patient survival. Our results may also be the first step (form the basis and provide the resources) in the development of computational and/or statistical approaches/tools dedicated to the identification of cancerdriver miRNA genes. The results published here are based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by research grants from the Polish National Science Centre [2016/22/A/NZ2/00184 (to P.K.) and 2015/17/N/NZ3/03629 (to M.O.U-T.)] Authors contributions MUTparticipated in conceiving the study, wrote all the scripts, performed most of the computational and statistical analyses, drafted the manuscript, prepared figures, tables, and supplementary materials; PGMparticipated in conceiving the study, discussed the study on all steps of analyses, participated in manuscript preparation, performed some analyses (3D structures); PNdiscussed the analyses on all steps of the study, performed some analyses, participated in manuscript preparation; EKperformed the sequencing experiments, critically read and corrected manuscript; SSperformed the sequencing experiments, critically read and corrected manuscript; MGprovided samples for the hsa-miR-1324 and hsa-miR-142 sequencing validation experiments, advised on hematological neoplasms and head and neck cancer, critically read and corrected manuscript; PKreceived financing, participated in conceiving the study, supervised and coordinated the study, drafted the manuscript (with MUT).

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A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme

Cited by 61 publications

References 55 publications

Modulation of ADARs mRNA expression in congenital heart defect patients

Modulation of ADARs mRNA expression in congenital heart defect patients

Deciphering miRNAs’ Action through miRNA Editing

Pan-Cancer analysis of somatic mutations in miRNA genes

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