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Cardiac Disease Status Dictates Functional mRNA Targeting Profiles of Individual MicroRNAs.

ABSTRACT: MicroRNAs are key players in cardiac stress responses, but the mRNAs, whose abundance and translational potential are primarily affected by changes in cardiac microRNAs, are not well defined. Stimulus-induced, large-scale alterations in the cardiac transcriptome, together with consideration of the law of mass action, further suggest that the mRNAs most substantively targeted by individual microRNAs will vary between unstressed and stressed conditions. To test the hypothesis that microRNA target profiles differ in health and disease, we traced the fate of empirically determined miR-133a and miR-378 targets in mouse hearts undergoing pressure overload hypertrophy.Ago2 immunoprecipitation with RNA sequencing (RNA-induced silencing complex sequencing) was used for unbiased definition of microRNA-dependent and microRNA-independent alterations occurring among ?13 000 mRNAs in response to transverse aortic constriction (TAC). Of 37 direct targets of miR-133a defined in unstressed hearts (fold change ?25%, false discovery rate <0.02), only 4 (11%) continued to be targeted by miR-133a during TAC, whereas for miR-378 direct targets, 3 of 32 targets (9%) were maintained during TAC. Similarly, only 16% (for miR-133a) and 53% (for miR-378) of hundreds of indirectly affected mRNAs underwent comparable regulation, demonstrating that the effect of TAC on microRNA direct target selection resulted in widespread alterations of signaling function. Numerous microRNA-mediated regulatory events occurring exclusively during pressure overload revealed signaling networks that may be responsive to the endogenous decreases in miR-133a during TAC.Pressure overload-mediated changes in overall cardiac RNA content alter microRNA targeting profiles, reinforcing the need to define microRNA targets in tissue-, cell-, and status-specific contexts.

SUBMITTER: Matkovich SJ

PROVIDER: S-EPMC4681654 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Cardiac Disease Status Dictates Functional mRNA Targeting Profiles of Individual MicroRNAs.

Matkovich Scot J SJ Dorn Gerald W GW Grossenheider Tiffani C TC Hecker Peter A PA

Circulation. Cardiovascular genetics 20151109 6

<h4>Background</h4>MicroRNAs are key players in cardiac stress responses, but the mRNAs, whose abundance and translational potential are primarily affected by changes in cardiac microRNAs, are not well defined. Stimulus-induced, large-scale alterations in the cardiac transcriptome, together with consideration of the law of mass action, further suggest that the mRNAs most substantively targeted by individual microRNAs will vary between unstressed and stressed conditions. To test the hypothesis th ...[more]

PMID: 26553694

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Project description:BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs affecting the expression of target genes via translational repression or mRNA degradation mechanisms. With the increasing availability of mRNA and miRNA expression data, it might be possible to assess functional targets using the fact that a miRNA might down-regulate its target mRNAs. In this work we computed the correlation of expression profiles between miRNAs and target mRNAs using the NCI-60 expression data. The aim is to investigate whether the correlations between miRNA and mRNA expression profiles, either positive or negative, can be used to assist the identification of functional miRNA-mRNA relationships. RESULTS: Predicted miRNA-mRNA interactions were taken from TargetScan 4.1 and miRBase release 5. Pearson correlation coefficients between the miRNA and the mRNA expression profiles were computed using NCI-60 data. The correlation coefficients were then subject to the Benjamini and Hochberg correction. Our results show that the percentage of TargetScan-predicted miRNA-mRNA interactions having negative correlation in expression profiles is higher than that of miRBase-predicted pairs. Using the experimentally validated miRNA targets listed in TarBase, genes involved in mRNA degradation show more negative correlations between miRNA and mRNA expression profiles, comparing with genes involved in translational repression. Furthermore, correlation analysis for miRNAs and mRNAs transcribed from the same genes shows that correlations of expression profiles between intronic miRNAs and host genes tend to be positive. Finally we found that a target gene might be down-regulated by more than one miRNAs sharing the same seed region. CONCLUSION: Our results suggest that expression profiles can be used in the computational identification of functional miRNA-target associations. One can expect a higher chance of finding negatively correlated expression profiles for TargetScan-predicted interactions than for miRBase-predicted ones. With limited experimentally validated miRNA-target interactions, expression profiles can only serve as a supplementary role in finding interactions between miRNAs and mRNAs.

Dataset Information

Cardiac Disease Status Dictates Functional mRNA Targeting Profiles of Individual MicroRNAs.

Publications

Cardiac Disease Status Dictates Functional mRNA Targeting Profiles of Individual MicroRNAs.

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