A combined computational-experimental approach predicts human microRNA targets

Abstract

A new paradigm of gene expression regulation has emerged recently with the discovery of microRNAs (miRNAs). Most, if not all, miRNAs are thought to control gene expression, mostly by base pairing with miRNA-recognition elements (MREs) found in their messenger RNA (mRNA) targets. Although a large number of human miRNAs have been reported, many of their mRNA targets remain unknown. Here we used a combined bioinformatics and experimental approach to identify important rules governing miRNA-MRE recognition that allow prediction of human miRNA targets. We describe a computational program, "DIANA-microT", that identifies mRNA targets for animal miRNAs and predicts mRNA targets, bearing single MREs, for human and mouse miRNAs. bros 1999;Seggerson et al. 2002;Zeng et al. 2002;Doench et al. 2003). The manner by which a miRNA or siRNA base pairs with its mRNA target correlates with its function: if the complementarity between a miRNA and its target is extensive, the RNA target is cleaved (Hutvagner and Zamore 2002;Llave et al. 2002;Rhoades et al. 2002;Tang et al. 2003;Xie et al. 2003); if the complementarity is partial, the stability of the target mRNA in not affected but its translation is repressed (Olsen and Ambros 1999;Seggerson et al. 2002;Zeng et al. 2002;Doench et al. 2003). However, how general this correlation is and the factors and mechanisms that determine the function of any given miRNA are unknown.

Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells

“…Prostein was one of the targets of miR-126* predicted by PicTar [40] but not by a number of others, including DIANA [9] or Miranda [11]. The two predicted sites for miR-126* were both in the 3′UTR of prostein mRNA (Fig.…”

“…The miRNA guide strand exhibits imperfect complementarity with specific sequences in the 3′-untranslated region (3′UTR) of the target mRNA, and the resultant RISC represses translation [3][4][5]. The rules of miRNA-target recognition are not well-defined, although a perfect or near-perfect match with nucleotides 2-8 of the miRNA 5′-end (the 'seed' or 'core' region) is considered the most important requirement [6][7][8][9]. Thus, a given 3′UTR may contain binding sites for multiple miRNA species, and reciprocally, a given miRNA may have target sites on multiple mRNA 3′UTRσ.…”

Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues

“…Several algorithms have been used to address the participation of these specific miRNAs in the development of cancer through the dysregulation of oncogene (John et al, 2004;Kiriakidou et al, 2004). Using these algorithms, we listed cancer-related mRNA targets of miRNA (Table 4).…”

Principles and effects of microRNA-mediated post-transcriptional gene regulation

“…Another function of the 3 0 region of a miRNA is to give specificity to the members of miRNA families that share identical seeds but they diverge in their 3 0 sequences (Brennecke et al, 2005). The recognition of the principles of miRNA targeting accelerated the development and improvement of a series of bio-computational approaches to predict miRNA targets in animals that produced a remarkably large number of putative miRNA-regulated transcripts further emphasizing the significance of miRNAs (Enright et al, 2003;Stark et al, 2003;Kiriakidou et al, 2004;Lewis et al, 2005;Lall et al, 2006).…”