Widespread regulatory activity of vertebrate microRNA* species

被引:270
作者
Yang, Jr-Shiuan [5 ,6 ]
Phillips, Michael D. [4 ]
Betel, Doron [3 ]
Mu, Ping [2 ]
Ventura, Andrea [2 ]
Siepel, Adam C. [4 ]
Chen, Kevin C. [1 ]
Lai, Eric C. [6 ]
机构
[1] Rutgers State Univ, BioMaPS Inst Quantitat Biol, Piscataway, NJ 08854 USA
[2] Sloan Kettering Inst, Canc Biol & Genet Program, New York, NY 10065 USA
[3] Sloan Kettering Inst, Computat Biol Ctr, New York, NY 10065 USA
[4] Cornell Univ, Dept Biol Stat & Computat Biol, Triinst Program Computat Biol & Med, Ithaca, NY 14853 USA
[5] Cornell Univ, Weill Grad Sch Med Sci, Program Mol Biol, New York, NY 10065 USA
[6] Sloan Kettering Inst, Dept Dev Biol, New York, NY 10065 USA
关键词
3 ' UTR; microRNA*; post-transcriptional repression; TARGET PREDICTIONS; TUMOR-SUPPRESSOR; RNA INTERFERENCE; GENE-EXPRESSION; SIRNAS; IDENTIFICATION; RECOGNITION; MIR-34A; PROTEIN; TRANSCRIPTS;
D O I
10.1261/rna.2537911
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
An obligate intermediate during microRNA (miRNA) biogenesis is an similar to 22-nucleotide RNA duplex, from which the mature miRNA is preferentially incorporated into a silencing complex. Its partner miRNA* species is generally regarded as a passenger RNA, whose regulatory capacity has not been systematically examined in vertebrates. Our bioinformatic analyses demonstrate that a substantial fraction of miRNA* species are stringently conserved over vertebrate evolution, collectively exhibit greatest conservation in their seed regions, and define complementary motifs whose conservation across vertebrate 3'-UTR evolution is statistically significant. Functional tests of 22 miRNA expression constructs revealed that a majority could repress both miRNA and miRNA* perfect match reporters, and the ratio of miRNA: miRNA* sensor repression was correlated with the endogenous ratio of miRNA: miRNA* reads. Analysis of microarray data provided transcriptome-wide evidence for the regulation of seed-matched targets for both mature and star strand species of several miRNAs relevant to oncogenesis, including mir-17, mir-34a, and mir-19. Finally, 3'-UTR sensor assays and mutagenesis tests confirmed direct repression of five miR-19* targets via star seed sites. Overall, our data demonstrate that miRNA* species have demonstrable impact on vertebrate regulatory networks and should be taken into account in studies of miRNA functions and their contribution to disease states.
引用
收藏
页码:312 / 326
页数:15
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