Abstract
MicroRNAs (miRNAs) play an important role in the regulation of gene expression. Previous studies on miRNA functions mainly focused on their target sites in the 3′ untranslated regions (UTRs) of mRNAs. However, increasing evidence has revealed that miRNAs can also induce mRNA degradation and mediate translational repression via complementary interactions with the coding sequence (CDS) and 5′UTR of mRNAs. In this study, we developed a novel database, MtiBase, to facilitate the comprehensive exploration of CDS- and 5′UTR-located miRNA target sites identified from cross-linking immunoprecipitation sequencing (CLIP-Seq) datasets and to uncover their regulatory effects on mRNA stability and translation from expression profile datasets. By integrating 61 Argonaute protein-binding CLIP-Seq datasets and miRNA target sites predicted by five commonly used programs, we identified approximately 4 400 000 CDS-located and 470 000 5′UTR-located miRNA target sites. Moreover, we evaluated the regulatory effects of miRNAs on mRNA stability and translation using the data from 222 gene expression profiles, and 28 ribosome-protected fragment sequencing, and six pulsed stable isotope labeling with amino acids in culture. Finally, the effects of SNPs on the functions of miRNA target sites were systematically evaluated. Our study provides a useful tool for functional studies of miRNAs in regulating physiology and pathology.Database URL: http://mtibase.sysu.edu.cn
Highlights
MicroRNAs are 22-nucleotide endogenous RNAs that participate in important biological processes by regulating gene expression [1]
In addition to these target sites, cross-linking immunoprecipitation sequencing [CLIP-Seq, e.g. High-throughput sequencing together with UV (HITS)-CLIP, photoactivatable ribonucleoside-enhanced (PAR)-CLIP, iCLIP, cross-linking ligation and sequencing of hybrids (CLASH)] datasets have detected numerous Argonaute proteins (Ago)-binding regions within mRNA coding sequence (CDS) and 50UTR [12,13,14], which reveal the existence of numerous miRNA target sites in these regions
By analysing the 61 Ago CLIP-Seq datasets, we identified 260 000 and 34 000 Ago-binding regions within the CDS and 50UTR regions, respectively (Table 1)
Summary
MicroRNAs (miRNAs) are 22-nucleotide (nt) endogenous RNAs that participate in important biological processes by regulating gene expression [1]. MiRNAs have been shown to induce mRNA degradation and repress translation by hybridizing with the 30untranslated regions (UTR) of mRNAs [2]. MiR181 can hybridize with the CDS of tumor suppressors RBassociated KRAB zinc finger and retinoblastoma 1, and induce the degradation of their mRNAs [11]. In addition to these target sites, cross-linking immunoprecipitation sequencing [CLIP-Seq, e.g. High-throughput sequencing together with UV (HITS)-CLIP, photoactivatable ribonucleoside-enhanced (PAR)-CLIP, iCLIP, cross-linking ligation and sequencing of hybrids (CLASH)] datasets have detected numerous Ago-binding regions within mRNA CDS and 50UTR [12,13,14], which reveal the existence of numerous miRNA target sites in these regions. Identifying the functional sites within mRNA CDS and 50UTR may be of great significance in uncovering the comprehensive regulatory effects of miRNAs
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