scholarly journals A-to-I editing in the miRNA seed region regulates target mRNA selection and silencing efficiency

2014 ◽  
Vol 42 (15) ◽  
pp. 10050-10060 ◽  
Author(s):  
Hideaki Kume ◽  
Kimihiro Hino ◽  
Josephine Galipon ◽  
Kumiko Ui-Tei
Keyword(s):  
Gene Expression Regulation ◽  
Seed Region ◽  
Rna Sequences ◽  
Protein Coding ◽  
Adenosine Deaminases ◽  
Target Mrnas ◽  
Non Coding Rna ◽  
The Difference ◽  
Mirna Seed

Abstract Hydrolytic deamination of adenosine to inosine (A-to-I) by adenosine deaminases acting on RNA (ADARs) is a post-transcriptional modification which results in a discrepancy between genomic DNA and the transcribed RNA sequence, thus contributing to the diversity of the transcriptome. Inosine preferentially base pairs with cytidine, meaning that A-to-I modifications in the mRNA sequences may be observed as A-to-G substitutions by the protein-coding machinery. Genome-wide studies have revealed that the majority of editing events occur in non-coding RNA sequences, but little is known about their functional meaning. MiRNAs are small non-coding RNAs that regulate the expression of target mRNAs with complementarities to their seed region. Here, we confirm that A-to-I editing in the miRNA seed duplex globally reassigns their target mRNAs in vivo, and reveal that miRNA containing inosine in the seed region exhibits a different degree of silencing efficiency compared to the corresponding miRNA with guanosine at the same position. The difference in base-pairing stability, deduced by melting temperature measurements, between seed-target duplexes containing either C:G or I:C pairs may account for the observed silencing efficiency. These findings unequivocally show that C:G and I:C pairs are biologically different in terms of gene expression regulation by miRNAs.

scholarly journals Viral miRNA adaptor differentially recruits miRNAs to target mRNAs through alternative base-pairing

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Carlos Gorbea ◽  
Tim Mosbruger ◽  
David A Nix ◽  
Demián Cazalla
Keyword(s):  
Seed Region ◽  
Base Pairing ◽  
Recognition Mechanism ◽  
Target Mrnas ◽  
Non Coding Rna ◽  
Infected Cells ◽  
Nucleotide Resolution ◽  
Rna Interaction ◽  
General Method

HSUR2 is a viral non-coding RNA (ncRNA) that functions as a microRNA (miRNA) adaptor. HSUR2 inhibits apoptosis in infected cells by recruiting host miRNAs miR-142–3p and miR-16 to mRNAs encoding apoptotic factors. HSUR2’s target recognition mechanism is not understood. It is also unknown why HSUR2 utilizes miR-16 to downregulate only a subset of transcripts. We developed a general method for individual-nucleotide resolution RNA-RNA interaction identification by crosslinking and capture (iRICC) to identify sequences mediating interactions between HSUR2 and target mRNAs in vivo. Mutational analyses confirmed identified HSUR2-mRNA interactions and validated iRICC as a method that confidently determines sequences mediating RNA-RNA interactions in vivo. We show that HSUR2 does not display a ‘seed’ region to base-pair with most target mRNAs, but instead uses different regions to interact with different transcripts. We further demonstrate that this versatile mode of interaction via variable base-pairing provides HSUR2 with a mechanism for differential miRNA recruitment.

scholarly journals Predicting effective microRNA target sites in mammalian mRNAs

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Vikram Agarwal ◽  
George W Bell ◽  
Jin-Wu Nam ◽  
David P Bartel
Keyword(s):  
Regulatory Networks ◽  
Quantitative Model ◽  
Seed Region ◽  
Microrna Target ◽  
Functional Sites ◽  
Uv Crosslinking ◽  
Gene Regulatory ◽  
Mirna Seed ◽  
Better Than

MicroRNA targets are often recognized through pairing between the miRNA seed region and complementary sites within target mRNAs, but not all of these canonical sites are equally effective, and both computational and in vivo UV-crosslinking approaches suggest that many mRNAs are targeted through non-canonical interactions. Here, we show that recently reported non-canonical sites do not mediate repression despite binding the miRNA, which indicates that the vast majority of functional sites are canonical. Accordingly, we developed an improved quantitative model of canonical targeting, using a compendium of experimental datasets that we pre-processed to minimize confounding biases. This model, which considers site type and another 14 features to predict the most effectively targeted mRNAs, performed significantly better than existing models and was as informative as the best high-throughput in vivo crosslinking approaches. It drives the latest version of TargetScan (v7.0; targetscan.org), thereby providing a valuable resource for placing miRNAs into gene-regulatory networks.

scholarly journals A functional non-coding RNA is produced from xbp-1 mRNA

2020 ◽  
Author(s):  
Xiao Liu ◽  
Jean-Denis Beaudoin ◽  
Carrie Ann Davison ◽  
Sara G. Kosmaczewski ◽  
Benjamin I. Meyer ◽  
...  
Keyword(s):  
Axon Regeneration ◽  
Biologically Active ◽  
Protein Coding ◽  
Unfolded Protein ◽  
Mrna Cleavage ◽  
Non Coding Rna ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Fine Tune

AbstractThe xbp-1 mRNA encodes the XBP-1 transcription factor, a critical part of the unfolded protein response. Here we report that an RNA fragment produced from xbp-1 mRNA cleavage is a biologically active non-coding RNA (ncRNA) in Caenorhabditis elegans neurons, providing the first example of ncRNA derived from mRNA cleavage. We show that the xbp-1 ncRNA is crucial for axon regeneration in vivo, and that it acts independently of the protein-coding function of the xbp-1 transcript. Structural analysis indicates that the function of the xbp-1 ncRNA depends on a single RNA stem; and this stem forms only in the cleaved xbp-1 ncRNA fragment. Disruption of this stem abolishes the non-coding but not coding function of the endogenous xbp-1 transcript. Thus, cleavage of the xbp-1 mRNA bifurcates it into a coding and a non-coding pathway; modulation of the two pathways may allow neurons to fine-tune their response to injury and other stresses.Graphic abstract

scholarly journals Long Non-coding RNA DANCR in Cancer: Roles, Mechanisms, and Implications

2021 ◽  
Vol 9 ◽  
Author(s):  
Maoye Wang ◽  
Jianmei Gu ◽  
Xu Zhang ◽  
Jianping Yang ◽  
Xiaoxin Zhang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Many Body ◽  
Protein Coding ◽  
Cancer Breast ◽  
Non Coding Rna ◽  
Mirna Sponges ◽  
Tumor Growth And Metastasis ◽  
Long Non Coding Rna

Long non-coding RNA (lncRNA) DANCR (also known as ANCR)—differentiation antagonizing non-protein coding RNA, was first reported in 2012 to suppress differentiation of epithelial cells. Emerging evidence demonstrates that DANCR is a cancer-associated lncRNA abnormally expressed in many cancers (e.g., lung cancer, gastric cancer, breast cancer, hepatocellular carcinoma). Increasing studies suggest that the dysregulation of DANCR plays critical roles in cancer cell proliferation, apoptosis, migration, invasion, and chemoresistance in vitro and tumor growth and metastasis in vivo. Mechanistic analyses show that DANCR can serve as miRNA sponges, stabilize mRNAs, and interact with proteins. Recent research reveals that DANCR can be detected in many body fluids such as serum, plasma, and exosomes, providing a quick and convenient method for cancer monitor. Thus DANCR can be used as a promising diagnostic and prognostic biomarker and therapeutic target for various types of cancer. This review focuses on the role and mechanism of DANCR in cancer progression with an emphasis on the clinical significance of DANCR in human cancers.

scholarly journals Epigenetic Regulation of Alternative mRNA Splicing in Dilated Cardiomyopathy

2020 ◽  
Vol 9 (5) ◽  
pp. 1499 ◽  
Author(s):  
Weng-Tein Gi ◽  
Jan Haas ◽  
Farbod Sedaghat-Hamedani ◽  
Elham Kayvanpour ◽  
Rewati Tappu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dilated Cardiomyopathy ◽  
Gene Expression Regulation ◽  
Strong Association ◽  
Mrna Splicing ◽  
Environment Interaction ◽  
Protein Coding ◽  
Genetic Imprinting ◽  
Non Coding Rna ◽  
Alternative Mrna Splicing

In recent years, the genetic architecture of dilated cardiomyopathy (DCM) has been more thoroughly elucidated. However, there is still insufficient knowledge on the modifiers and regulatory principles that lead to the failure of myocardial function. The current study investigates the association of epigenome-wide DNA methylation and alternative splicing, both of which are important regulatory principles in DCM. We analyzed screening and replication cohorts of cases and controls and identified distinct transcriptomic patterns in the myocardium that differ significantly, and we identified a strong association of intronic DNA methylation and flanking exons usage (p < 2 × 10−16). By combining differential exon usage (DEU) and differential methylation regions (DMR), we found a significant change of regulation in important sarcomeric and other DCM-associated pathways. Interestingly, inverse regulation of Titin antisense non-coding RNA transcript splicing and DNA methylation of a locus reciprocal to TTN substantiate these findings and indicate an additional role for non-protein-coding transcripts. In summary, this study highlights for the first time the close interrelationship between genetic imprinting by DNA methylation and the transport of this epigenetic information towards the dynamic mRNA splicing landscape. This expands our knowledge of the genome–environment interaction in DCM besides simple gene expression regulation.

scholarly journals Potential Role of miRNAs in the Acquisition of Chemoresistance in Neuroblastoma

2021 ◽  
Vol 11 (2) ◽  
pp. 107
Author(s):  
Barbara Marengo ◽  
Alessandra Pulliero ◽  
Maria Valeria Corrias ◽  
Riccardo Leardi ◽  
Emanuele Farinini ◽  
...  
Keyword(s):  
Causes Of Death ◽  
Potential Role ◽  
Principal Component ◽  
Analysis Data ◽  
Mycn Amplification ◽  
Rna Sequences ◽  
Primary Tumors ◽  
Non Coding Rna

Neuroblastoma (NB) accounts for about 8–10% of pediatric cancers, and the main causes of death are the presence of metastases and the acquisition of chemoresistance. Metastatic NB is characterized by MYCN amplification that correlates with changes in the expression of miRNAs, which are small non-coding RNA sequences, playing a crucial role in NB development and chemoresistance. In the present study, miRNA expression was analyzed in two human MYCN-amplified NB cell lines, one sensitive (HTLA-230) and one resistant to Etoposide (ER-HTLA), by microarray and RT-qPCR techniques. These analyses showed that miRNA-15a, -16-1, -19b, -218, and -338 were down-regulated in ER-HTLA cells. In order to validate the presence of this down-regulation in vivo, the expression of these miRNAs was analyzed in primary tumors, metastases, and bone marrow of therapy responder and non-responder pediatric patients. Principal component analysis data showed that the expression of miRNA-19b, -218, and -338 influenced metastases, and that the expression levels of all miRNAs analyzed were higher in therapy responders in respect to non-responders. Collectively, these findings suggest that these miRNAs might be involved in the regulation of the drug response, and could be employed for therapeutic purposes.

scholarly journals The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function

2019 ◽  
Author(s):  
Hao Chen ◽  
Zhennan Shi ◽  
Jiaojiao Guo ◽  
Kao-jung Chang ◽  
Qianqian Chen ◽  
...  
Keyword(s):  
Mitochondrial Protein ◽  
Small Subunit ◽  
12S Rrna ◽  
Mitochondrial Rna ◽  
Protein Coding ◽  
Mitochondrial Ribosome ◽  
The Difference ◽  
And Function

ABSTRACTMitochondrial DNA (mtDNA) gene expression is coordinately regulated pre- and post-transcriptionally, and its perturbation can lead to human pathologies. Mitochondrial ribosomal RNAs (mt-rRNAs) undergo a series of nucleotide modifications following release from polycistronic mitochondrial RNA (mtRNA) precursors, which is essential for mitochondrial ribosomal biogenesis. Cytosine N4 methylation (m4C) at position 839 of the 12S small subunit (SSU) mt-rRNA was identified decades ago, however, its biogenesis and function have not been elucidated in details. Here we demonstrate that human Methyltransferase Like 15 (METTL15) is responsible for 12S mt-rRNA methylation at C839 (m4C839) both in vivo and in vitro. We tracked the evolutionary history of RNA m4C methyltransferases and revealed the difference in substrates preference between METTL15 and its bacterial ortholog rsmH. Additionally, unlike the very modest impact on ribosome upon loss of m4C methylation in bacterial SSU rRNA, we found that depletion of METTL15 specifically causes severe defects in mitochondrial ribosome assembly, which leads to an impaired translation of mitochondrial protein-coding genes and a decreased mitochondrial respiration capacity. Our findings point to a co-evolution of methylatransferase specificities and modification patterns in rRNA with differential impact on prokaryotic ribosome versus eukaryotic mitochondrial ribosome.

scholarly journals From life to death: microRNAs in the fine tuning of the heart

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Sayantan Nath ◽  
S I Rizvi ◽  
Munish Kumar
Keyword(s):  
Fine Tuning ◽  
Untranslated Regions ◽  
Seed Region ◽  
Cardiovascular Disorders ◽  
Cardiovascular Development ◽  
Rna Sequences ◽  
Mrna Targets ◽  
Mirna Seed ◽  
Potential Therapeutics ◽  
Specific Mrna

AbstractThe heart is one of the most important vital organs, and any malfunctioning of the heart and its blood vessels may contribute to cardiovascular disorders. Diseases of the cardiovascular system represent the most common cause of human morbidity and mortality around the globe. Thus, there is always a need for innovative new therapies and diagnostics for cardiovascular disorders. In the past decades, a plethora of tiny, endogenous, singlestranded RNA sequences called microRNAs (miRNAs) has been studied meticulously in cardiovascular development and pathophysiology, providing a new dimension to the heart’s biology. miRNAs posttranscriptional inhibit the gene expression of specific mRNA targets through Watson– Crick base pairing between the miRNA “seed region” and the 3′ untranslated regions (UTRs) of target mRNAs. Better recognized as “master switches”, miRNAs are emerging as vital regulators of mammalian cardiovascular development and disease and thus are helpful in understanding therapeutic targets and diagnostics for a variety of cardiovascular disorders. In this review, a detailed discussion of the roles of various microRNAs in cardiovascular development and pathophysiology with potential therapeutics is considered.

scholarly journals Critical contribution of 3' non-seed base pairing to the in vivo function of the evolutionarily conserved let-7a microRNA

2021 ◽  
Author(s):  
Ye Duan ◽  
Isana Veksler-Lublinsky ◽  
Victor Ambros
Keyword(s):  
Systematic Investigation ◽  
Seed Region ◽  
Seed Sequence ◽  
Base Pairing ◽  
Non Coding Rna ◽  
Evolutionarily Conserved ◽  
Microrna Function

MicroRNAs are endogenous regulatory non-coding RNA that exist in all multi-cellular organisms. Base-pairing of the seed region (g2-g8) is essential for microRNA targeting, however the in vivo functions of 3' non-seed region (g9-g22) are less well understood. Here we report the first systematic investigation of the in vivo roles of 3' non-seed nucleotides in microRNA let-7a, whose entire g9-g22 region is conserved among bilaterians. We found that the 3' non-seed sequence functionally distinguishes let-7a from its family paralogs. The complete pairing of g11-g16 is essential for let-7a to fully repress multiple key targets in vivo, including evolutionarily conserved lin-41, daf-12 and hbl-1. Nucleotides at g17-g22 are less critical but may compensate for mismatches in the g11-g16 region. Interestingly, we find that 3' non-seed pairing of let-7a can be functionally required even with sites that permit perfect seed pairing. These results provide evidence that the specific configurations of both seed and 3' non-seed base-pairing can critically influence microRNA function in vivo.

scholarly journals Downregulation of long non-coding RNA AIRN promotes mitophagy in alcoholic fatty hepatocytes by promoting ubiquitination of mTOR

2021 ◽  
pp. 245-253
Author(s):  
Sujian Shen ◽  
Jianzhang Wang ◽  
Li miao Lin
Keyword(s):  
Protein Level ◽  
Treatment Time ◽  
Protein Coding ◽  
Alcoholic Fatty Liver ◽  
Non Coding Rna ◽  
Rna Immunoprecipitation ◽  
Mtor Protein ◽  
The Difference ◽  
Student’S T ◽  
Long Non Coding Rna

Long non-coding RNAs (lncRNAs) are crucial in chronic liver diseases, but the specific molecular mechanism of lncRNAs in alcoholic fatty liver (AFL) remains unclear. In this study, we investigated the in-depth regulatory mechanism of mTOR affected by AIRN non-protein coding RNA (lncRNA-AIRN) in the development of AFL. LncRNA-AIRN was highly expressed in the liver tissues of AFL C57BL/6 mice and oleic acid+alcohol (O+A) treated AML-12 cells by using quantitative real-time PCR. RNA pull-down and RNA immunoprecipitation experiments demonstrated that there was an interaction between lncRNA-AIRN and mTOR, and that interference with lncRNA-AIRN could promote the mTOR protein level. Results of cycloheximide-chase assay showed that the protein level of mTOR was decreased with the treatment time after the knockdown of lncRNA-AIRN. Furthermore, the knockdown of lncRNA-AIRN reduced mTOR protein level by promoting the E3 ubiquitin ligase FBXW7-mediated ubiquitination. The lncRNA-AIRN/mTOR axis was involved in the regulation of the mitophagy of O+A treated hepatocytes, which was confirmed by the cell transfection and the MTT assay. SPSS 16.0 was used for analyzing data. The difference between the two groups was analyzed by performing Student’s t-test, and ANOVA was used to analyze the difference when more than two groups. P values < 0.05 were considered to be significantly different. Our findings demonstrated that the knockdown of lncRNA-AIRN influenced mitophagy in AFL by promoting mTOR ubiquitination.

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