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Grzegorz Rorbach, Olgierd Unold, Bogumil M Konopka
Mirtrons are non-canonical microRNAs encoded in introns the biogenesis of which starts with splicing. They are not processed by Drosha and enter the canonical pathway at the Exportin-5 level. Mirtrons are much less evolutionary conserved than canonical miRNAs. Due to the differences, canonical miRNA predictors are not applicable to mirtron prediction. Identification of differences is important for designing mirtron prediction algorithms and may help to improve the understanding of mirtron functioning. So far, only simple, single-feature comparisons were reported...
May 15, 2018: Scientific Reports
Igor I Titov, Pavel S Vorozheykin
BACKGROUND: MicroRNAs proceeds through the different canonical and non-canonical pathways; the most frequent of the non-canonical ones is the splicing-dependent biogenesis of mirtrons. We compare the mirtrons and non-mirtrons of human and mouse to explore how their maturation appears in the precursor structure around the miRNA. RESULTS: We found the coherence of the overhang lengths what indicates the dependence between the cleavage sites. To explain this dependence we suggest the 2-lever model of the Dicer structure that couples the imprecisions in Drosha and Dicer...
February 9, 2018: BMC Genomics
Jaaved Mohammed, Alex S Flynt, Alexandra M Panzarino, Md Mosharrof Hossein Mondal, Matthew DeCruz, Adam Siepel, Eric C Lai
To assess miRNA evolution across the Drosophila genus, we analyzed several billion small RNA reads across 12 fruit fly species. These data permit comprehensive curation of species- and clade-specific variation in miRNA identity, abundance, and processing. Among well-conserved miRNAs, we observed unexpected cases of clade-specific variation in 5' end precision, occasional antisense loci, and putatively noncanonical loci. We also used strict criteria to identify a large set (649) of novel, evolutionarily restricted miRNAs...
January 2018: Genome Research
Eiko Sakai, Yusuke Miura, Emi Suzuki-Kouyama, Kengo Oka, Masashi Tachibana, Kenji Kawabata, Fuminori Sakurai, Hiroyuki Mizuguchi
Angiogenesis, new vessel formation from pre-existing vessels, is a highly conserved event through vertebrates. However, the system for tuning angiogenesis by species-intrinsic factors is totally unknown. miR-1224 is a member of mammal-specific mirtrons, which were identified as non-canonical microRNAs. We found that the expression of miR-1224 was upregulated in capillary-like tube-forming human umbilical vein endothelial cells on Matrigel. Enforced expression of miR-1224 stimulated tube formation, whereas repression of endogenous miR-1224 inhibited formation...
July 17, 2017: Scientific Reports
Helen J Curtis, Yiqi Seow, Matthew J A Wood, Miguel A Varela
We evaluate a knockdown-replacement strategy mediated by mirtrons as an alternative to allele-specific silencing using spinocerebellar ataxia 7 (SCA7) as a model. Mirtrons are introns that form pre-microRNA hairpins after splicing, producing RNAi effectors not processed by Drosha. Mirtron mimics may therefore avoid saturation of the canonical processing pathway. This method combines gene silencing mediated by an artificial mirtron with delivery of a functional copy of the gene such that both elements of the therapy are always expressed concurrently, minimizing the potential for undesirable effects and preserving wild-type function...
July 27, 2017: Nucleic Acids Research
Florent Hubé, Damien Ulveling, Alain Sureau, Sabrina Forveille, Claire Francastel
Introns represent almost half of the human genome, although they are eliminated from transcripts through RNA splicing. Yet, different classes of non-canonical miRNAs have been proposed to originate directly from intron splicing. Here, we considered the alternative splicing of introns as an interesting source of miRNAs, compatible with a developmental switch. We report computational prediction of new Short Intron-Derived ncRNAs (SID), defined as precursors of smaller ncRNAs like miRNAs and snoRNAs produced directly by splicing, and tested their dependence on each key factor in canonical or alternative miRNAs biogenesis (Drosha, DGCR8, DBR1, snRNP70, U2AF65, PRP8, Dicer, Ago2)...
May 5, 2017: Nucleic Acids Research
Perrine Rasschaert, Thomas Figueroa, Ginette Dambrine, Denis Rasschaert, Sylvie Laurent
Interplay between alternative splicing and the Microprocessor may have differential effects on the expression of intronic miRNAs organized into clusters. We used a viral model - the LAT long non-coding RNA (LAT lncRNA) of Marek's disease oncogenic herpesvirus (MDV-1), which has the mdv1-miR-M8-M6-M7-M10 cluster embedded in its first intron - to assess the impact of splicing modifications on the biogenesis of each of the miRNAs from the cluster. Drosha silencing and alternative splicing of an extended exon 2 of the LAT lncRNA from a newly identified 3' splice site (SS) at the end of the second miRNA of the cluster showed that mdv1-miR-M6 was a 5'-tailed mirtron...
December 2016: RNA Biology
Thomas B Hansen, Morten T Venø, Trine I Jensen, Anne Schaefer, Christian K Damgaard, Jørgen Kjems
MicroRNAs (miRNAs) are short (∼22 nucleotides) regulators of gene expression acting by direct base pairing to 3'-UTR target sites in messenger RNAs. Mature miRNAs are produced by two sequential endonucleolytic cleavages facilitated by Drosha in the nucleus and Dicer in the cytoplasm. A subclass of miRNAs, termed mirtrons, derives from short introns and enters the miRNA biogenesis pathway as Dicer substrates. Here we uncover a third biogenesis strategy that, similar to mirtron biogenesis, initiates from short introns but bypasses Dicer cleavage...
2016: Nature Communications
Luca Penso-Dolfin, Ross Swofford, Jeremy Johnson, Jessica Alföldi, Kerstin Lindblad-Toh, David Swarbreck, Simon Moxon, Federica Di Palma
The domestic dog, Canis familiaris, is a valuable model for studying human diseases. The publication of the latest Canine genome build and annotation, CanFam3.1 provides an opportunity to enhance our understanding of gene regulation across tissues in the dog model system. In this study, we used the latest dog genome assembly and small RNA sequencing data from 9 different dog tissues to predict novel miRNAs in the dog genome, as well as to annotate conserved miRNAs from the miRBase database that were missing from the current dog annotation...
2016: PloS One
M Yu Skurnikov, Yu A Makarova, E N Knyazev, K A Fomicheva, K M Nyushko, E K Saribekyan, B Ya Alekseev, A D Kaprin
Analysis of the plasma microRNA profile can be used for the diagnosis of various pathological and physiological conditions. Complete microRNA microprofiling is an extremely important task. Here we used microarray analysis allowing measurement of the expression of 2500 microRNA (MirBase, version 20). About 10% known microRNA were found in the plasma. Most of the detected microRNA (69 microRNA; ~30%) were encoded by mirtrons.
March 2016: Bulletin of Experimental Biology and Medicine
Stasė Butkytė, Laurynas Čiupas, Eglė Jakubauskienė, Laurynas Vilys, Paulius Mocevicius, Arvydas Kanopka, Giedrius Vilkaitis
BACKGROUND: An abundant class of intronic microRNAs (miRNAs) undergoes atypical Drosha-independent biogenesis in which the spliceosome governs the excision of hairpin miRNA precursors, called mirtrons. Although nearly 500 splicing-dependent miRNA candidates have been recently predicted via bioinformatic analysis of human RNA-Seq datasets, only a few of them have been experimentally validated. The detailed mechanism of miRNA processing by the splicing machinery and the roles of mirtronic miRNAs in cancer are yet to be uncovered...
2016: Clinical Epigenetics
Derya Aslan, Christian Garde, Mette Katrine Nygaard, Alexandra Søgaard Helbo, Konstantinos Dimopoulos, Jakob Werner Hansen, Marianne Tang Severinsen, Marianne Bach Treppendahl, Lene Dissing Sjø, Kirsten Grønbæk, Lasse Sommer Kristensen
Spliceosome mutations are frequently observed in patients with myelodysplastic syndromes (MDS). However, it is largely unknown how these mutations contribute to the disease. MicroRNAs (miRNAs) are small noncoding RNAs, which have been implicated in most human cancers due to their role in post transcriptional gene regulation. The aim of this study was to analyze the impact of spliceosome mutations on the expression of miRNAs in a cohort of 34 MDS patients. In total, the expression of 76 miRNAs, including mirtrons and splice site overlapping miRNAs, was accurately quantified using reverse transcriptase quantitative PCR...
March 1, 2016: Oncotarget
Jiayu Wen, Erik Ladewig, Sol Shenker, Jaaved Mohammed, Eric C Lai
Mirtrons are microRNA (miRNA) substrates that utilize the splicing machinery to bypass the necessity of Drosha cleavage for their biogenesis. Expanding our recent efforts for mammalian mirtron annotation, we use meta-analysis of aggregate datasets to identify ~500 novel mouse and human introns that confidently generate diced small RNA duplexes. These comprise nearly 1000 total loci distributed in four splicing-mediated biogenesis subclasses, with 5'-tailed mirtrons as, by far, the dominant subtype. Thus, mirtrons surprisingly comprise a substantial fraction of endogenous Dicer substrates in mammalian genomes...
September 2015: PLoS Computational Biology
Olivia S Rissland
In this issue of Molecular Cell, Bortolamiol-Becet et al. (2015) and Reimão-Pinto et al. (2015) show that in flies Tailor preferentially uridylates mirtron pre-miRNA hairpins to suppress their biogenesis.
July 16, 2015: Molecular Cell
Madalena M Reimão-Pinto, Valentina Ignatova, Thomas R Burkard, Jui-Hung Hung, Raphael A Manzenreither, Ivica Sowemimo, Veronika A Herzog, Brian Reichholf, Sara Fariña-Lopez, Stefan L Ameres
Uridylation of RNA species represents an emerging theme in post-transcriptional gene regulation. In the microRNA pathway, such modifications regulate small RNA biogenesis and stability in plants, worms, and mammals. Here, we report Tailor, an uridylyltransferase that is required for the majority of 3' end modifications of microRNAs in Drosophila and predominantly targets precursor hairpins. Uridylation modulates the characteristic two-nucleotide 3' overhang of microRNA hairpins, which regulates processing by Dicer-1 and destabilizes RNA hairpins...
July 16, 2015: Molecular Cell
Diane Bortolamiol-Becet, Fuqu Hu, David Jee, Jiayu Wen, Katsutomo Okamura, Ching-Jung Lin, Stefan L Ameres, Eric C Lai
Several terminal uridyltransferases (TUTases) are known to modulate small RNA biogenesis and/or function via diverse mechanisms. Here, we demonstrate that Drosophila splicing-derived pre-miRNAs (mirtrons) are efficiently modified by the previously uncharacterized TUTase, Tailor. Tailor is necessary and sufficient for mirtron hairpin uridylation, and this modification inhibits mirtron biogenesis. Genome-wide analyses demonstrate that mirtrons are dominant Tailor substrates, and three features contribute to substrate specificity...
July 16, 2015: Molecular Cell
Kian Hong Kock, Kiat Whye Kong, Shawn Hoon, Yiqi Seow
Mirtrons are introns that form pre-miRNA hairpins after splicing to produce RNA interference (RNAi) effectors distinct from Drosha-dependent intronic miRNAs, and will be especially useful for co-delivery of coding genes and RNAi. A specific family of mirtrons - 3'-tailed mirtrons - has hairpins precisely defined on the 5' end by the 5' splice site and 3' end by the branch point. Here, we present design principles for artificial 3'-tailed mirtrons and demonstrate, for the first time, efficient gene knockdown with tailed mirtrons within eGFP coding region...
July 27, 2015: Nucleic Acids Research
Jingping Qin, Xiaoxia Ma, Zili Yi, Zhonghai Tang, Yijun Meng
Recent research has linked the non-coding intronic regions of plant genes to the production of small RNAs (sRNAs). Certain introns, called 'mirtrons' and 'sirtrons', could serve as the single-stranded RNA precursors for the generation of microRNA and small interfering RNA, respectively. However, whether the intronic regions could serve as the template for double-stranded RNA synthesis and then for sRNA biogenesis through an RDR (RNA-dependent RNA polymerase)-dependent pathway remains unclear. In this study, a genome-wide search was made for the RDR-dependent sRNA loci within the intronic regions of the Arabidopsis genes...
April 2015: Journal of Experimental Botany
XiaoLei Ding, JianRen Ye, XiaoQin Wu, Lin Huang, LiHua Zhu, SiXi Lin
Bursaphelenchus xylophilus is known as the causative agent of pine wilt disease with complex life cycles. In this research, four small RNA libraries derived from different infection stages of pine wilt disease were constructed and sequenced. Consequently, we obtained hundreds of evolutionarily conserved miRNAs and novel miRNA candidates. The analysis of miRNA expression patterns showed that most miRNAs were expressed at extraordinarily high levels during the middle stage of pine wilt disease. Functional analysis revealed that expression levels of miR-73 and miR-239 were mutually exclusive with their target GH45 cellulase genes...
January 25, 2015: Gene
Jia Han Deng, Peter Deng, Shi-Lung Lin, Shao-Yao Ying
MicroRNAs (miRNAs) are small, single-stranded noncoding RNAs important in many biological processes through posttranscriptional modification of complementary intracellular messenger RNAs (mRNAs). MiRNAs have been reported to induce RNA interference (RNAi), by utilizing the miRNA-induced silencing complex (miRISC) to target mRNAs. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome...
2015: Methods in Molecular Biology
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