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Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms.

ABSTRACT: Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes.Here we introduce InMiR, a new computational method that uses a linear-Gaussian model to predict the targets of intronic miRNAs based on the expression profiles of their host genes across a large number of datasets. Our method recovers nearly twice as many true positives at the same fixed false positive rate as a comparable method that only considers correlations. Through an analysis of 140 Affymetrix datasets from Gene Expression Omnibus, we build a network of 19,926 interactions among 57 intronic miRNAs and 3,864 targets. InMiR can also predict which host genes have expression profiles that are good surrogates for those of their intronic miRNAs. Host genes that InMiR predicts are bad surrogates contain significantly more miRNA target sites in their 3' UTRs and are significantly more likely to have predicted Pol II and Pol III promoters in their introns.We provide a dataset of 1,935 predicted mRNA targets for 22 intronic miRNAs. These prediction are supported both by sequence features and expression. By combining our results with previous reports, we distinguish three classes of intronic miRNAs: Those that are tightly regulated with their host gene; those that are likely to be expressed from the same promoter but whose host gene is highly regulated by miRNAs; and those likely to have independent promoters.

SUBMITTER: Radfar MH

PROVIDER: S-EPMC3111417 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms.

Radfar M Hossein MH Wong Willy W Morris Quaid Q

PloS one 20110609 6

Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it ...[more]

PMID: 21694770

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Project description:Triticum aestivum (wheat), a major staple food grain, is affected by various biotic stresses. Among these, fungal diseases cause about 15-20% of yield loss, worldwide. In this study, we performed a comparative analysis of protein-protein interactions between two Puccinia graminis races (Pgt 21-0 and Pgt Ug99) that cause stem (black) rust in wheat. The available molecular techniques to study the host-pathogen interaction mechanisms are expensive and labor-intensive. We implemented two computational approaches (interolog and domain-based) for the prediction of PPIs and performed various functional analysis to determine the significant differences between the two pathogen races. The analysis revealed that T. aestivum-Pgt 21-0 and T. aestivum-Pgt Ug99 interactomes consisted of ∼90M and ∼56M putative PPIs, respectively. In the predicted PPIs, we identified 115 Pgt 21-0 and 34 Pgt Ug99 potential effectors that were highly involved in pathogen virulence and development. Functional enrichment analysis of the host proteins revealed significant GO terms and KEGG pathways such as O-methyltransferase activity (GO:0008171), regulation of signal transduction (GO:0009966), lignin metabolic process (GO:0009808), plastid envelope (GO:0009526), plant-pathogen interaction pathway (ko04626), and MAPK pathway (ko04016) that are actively involved in plant defense and immune signaling against the biotic stresses. Subcellular localization analysis anticipated the host plastid as a primary target for pathogen attack. The highly connected host hubs in the protein interaction network belonged to protein kinase domain including Ser/Thr protein kinase, MAPK, and cyclin-dependent kinase. We also identified 5,577 transcription factors in the interactions, associated with plant defense during biotic stress conditions. Additionally, novel host targets that are resistant to stem rust disease were also identified. The present study elucidates the functional differences between Pgt 21-0 and Pgt Ug99, thus providing the researchers with strain-specific information for further experimental validation of the interactions, and the development of durable, disease-resistant crop lines.

Project description:BACKGROUND: MicroRNA are a class of small RNAs that regulate gene expression by inhibiting translation of protein encoding transcripts through targeting of a microRNA-protein complex by base-pairing of the microRNA sequence to cognate recognition sequences in the 3' untranslated region (UTR) of the mRNA. Target identification for a given microRNA sequence is generally accomplished by informatics analysis of predicted mRNA sequences present in the genome or in databases of transcript sequence for the tissue of interest. However, gene models for porcine skeletal muscle transcripts in current databases, specifically complete sequence of the 3' UTR, are inadequate for this exercise. METHODOLOGY/PRINCIPAL FINDINGS: To provide data necessary to identify gene targets for microRNA in porcine skeletal muscle, normalized cDNA libraries were sequenced using Roche 454 GS-FLX pyrosequencing and de novo assembly of transcripts enriched in the 3' UTR was performed using the MIRA sequence assembly program. Over 725 million bases of sequence were generated, which assembled into 18,202 contigs. Sequence reads were mapped to a 3' UTR database containing porcine sequences. The 3' UTR that mapped to the database were examined to predict targets for previously identified microRNA that had been separately sequenced from the same porcine muscle sample used to generate the cDNA libraries. For genes with microRNA-targeted 3' UTR, KEGG pathways were computationally determined in order to identify potential functional effects of these microRNA-targeted transcripts. CONCLUSIONS: Through next-generation sequencing of transcripts expressed in skeletal muscle, mapping reads to a 3' UTR database, and prediction of microRNA target sites in the 3' UTR, our results identified genes expressed in porcine skeletal muscle and predicted the microRNA that target these genes. Additionally, identification of pathways regulated by these microRNA-targeted genes provides us with a set of genes that can be further evaluated for their potential role in skeletal muscle development and growth.

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Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms.

Publications

Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms.

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