New class of microRNA targets containing simultaneous 5′-UTR and 3′-UTR interaction sites

被引:438
作者
Lee, Inhan [1 ]
Ajay, Subramanian S. [2 ]
Yook, Jong In [3 ]
Kim, Hyun Sil [3 ]
Hong, Su Hyung [4 ]
Kim, Nam Hee [3 ]
Dhanasekaran, Saravana M. [5 ]
Chinnaiyan, Arul M. [5 ]
Athey, Brian D. [1 ,6 ]
机构
[1] Univ Michigan, Dept Psychiat, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Bioinformat Grad Program, Ann Arbor, MI 48109 USA
[3] Yonsei Univ, Coll Dent, Oral Canc Res Inst, Dept Oral Pathol, Seoul 120752, South Korea
[4] Kyungpook Natl Univ, Sch Dent, Dept Dent Microbiol, Taegu 700412, South Korea
[5] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA
[6] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA
基金
美国国家卫生研究院;
关键词
MESSENGER-RNA DEGRADATION; POSTTRANSCRIPTIONAL REGULATION; TRANSLATION; SPECIFICITY; MECHANISMS; REPRESSION; MAMMALS; MIRNAS; IMPACT; LET-7;
D O I
10.1101/gr.089367.108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
070307 [化学生物学]; 071010 [生物化学与分子生物学];
摘要
MicroRNAs (miRNAs) are known to post-transcriptionally regulate target mRNAs through the 3'-UTR, which interacts mainly with the 5'-end of miRNA in animals. Here we identify many endogenous motifs within human 5'-UTRs specific to the 3'-ends of miRNAs. The 3'-end of conserved miRNAs in particular has significant interaction sites in the human-enriched, less conserved 5'-UTR miRNA motifs, while human-specific miRNAs have significant interaction sites only in the conserved 5'-UTR motifs, implying both miRNA and 5'-UTR are actively evolving in response to each other. Additionally, many miRNAs with their 3'-end interaction sites in the 5'-UTRs turn out to simultaneously contain 5'-end interaction sites in the 3'-UTRs. Based on these findings we demonstrate combinatory interactions between a single miRNA and both end regions of an mRNA using model systems. We further show that genes exhibiting large-scale protein changes due to miRNA overexpression or deletion contain both UTR interaction sites predicted. We provide the predicted targets of this new miRNA target class, miBridge, as an efficient way to screen potential targets, especially for nonconserved miRNAs, since the target search space is reduced by an order of magnitude compared with the 3'-UTR alone. Efficacy is confirmed by showing SEC24D regulation with hsa-miR-605, a miRNA identified only in primate, opening the door to the study of nonconserved miRNAs. Finally, miRNAs (and associated proteins) involved in this new targeting class may prevent 40S ribosome scanning through the 5'-UTR and keep it from reaching the start-codon, preventing 60S association.
引用
收藏
页码:1175 / 1183
页数:9
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