Intronic microRNAs support their host genes by mediating synergistic and antagonistic regulatory effects - PubMed (original) (raw)

Intronic microRNAs support their host genes by mediating synergistic and antagonistic regulatory effects

Dominik Lutter et al. BMC Genomics. 2010.

Abstract

Background: MicroRNA-mediated control of gene expression via translational inhibition has substantial impact on cellular regulatory mechanisms. About 37% of mammalian microRNAs appear to be located within introns of protein coding genes, linking their expression to the promoter-driven regulation of the host gene. In our study we investigate this linkage towards a relationship beyond transcriptional co-regulation.

Results: Using measures based on both annotation and experimental data, we show that intronic microRNAs tend to support their host genes by regulation of target gene expression with significantly correlated expression patterns. We used expression data of three differentiating cell types and compared gene expression profiles of host and target genes. Many microRNA target genes show expression patterns significantly correlated with the expressions of the microRNA host genes. By calculating functional similarities between host and predicted microRNA target genes based on GO annotations, we confirm that many microRNAs link host and target gene activity in an either synergistic or antagonistic manner.

Conclusions: These two regulatory effects may result from fine tuning of target gene expression functionally related to the host or knock-down of remaining opponent target gene expression. This finding allows to extend the common practice of mapping large scale gene expression data to protein associated genes with functionality of co-expressed intronic microRNAs.

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Figures

Figure 1

Regulatory mechanisms. The two proposed regulatory mechanisms of functional host to miRNA relationships. (A) An antagonistic effect can be achieved by miRNA-mediated downregulation of a gene with perturbing effect on a pathway or biological process regulated by the host gene. (B) Synergistic effect by miRNA-mediated fine tuning of a target gene with common contribution of host and target gene to a pathway or biological process. Proposed corresponding gene expression patterns are shown below the two motif figures. Genes are marked by rounded rectangles, miRNAs by ellipses. Host and intronic miRNA relations are indicated by an edge with a dot. MiRNA target tuning regulation is indicated by a blank triangle, inhibition is indicated with a stop.

Figure 2

Clustered heat maps. Clustered heat maps for the seven host gene clusters (H) and the corresponding target gene expression profiles (T). For all three time course datasets only clusters with more than five host genes are shown. Each row corresponds to one gene expression pattern, each column to a measurement. Time dependent measurements are shown in ascending order from left to right. The expression level of each gene is standardized so that the mean is set to 0 and the standard deviation is 1. Expression levels above and below 0 are color-coded: red indicates for high and green for low expression levels, respectively; black for zero expression values. Biological replicates of the three datasets are in order from Rep. 1 to Rep. 2 and Rep. 3, respectively. Colored subtrees in the dendrogramm derived from hierarchical clustering denote for co-expressed (green) or anti-correlated (red) gene expression of predicted targets. (Somitogenesis) The dataset splits up into three host gene clusters, SG I with 13, SG II with 21, and SG III with 7 host genes. (Neurite Outgrowth) Two cluster with 10 (NO I) and 17 (NO II) host genes could be identified with similar behavior of host and target genes in both replicates. (Stem Cell Development) Two host gene clusters containing 9 (SCD I) and 8 (SCD II) host genes were identified. All host and target genes show similar behavior in all three replicates. For each dataset, flipped expression patterns between the host/target clusters are striking (SG I vs. SG II; NO I vs. NO II; SCD I vs. SCD III).

Figure 3

Results: expression analysis. Results of the host gene cluster based expression analysis. Grey bars denote the number of all identified host gene clusters including unclustered hosts with expressed target genes, predicted by Pictar (PT), TargetScan (TS), RNA22 (R) and our consensus model (CM). Orange bars denote the number of clusters with significantly correlated target gene expression patterns. The relative fraction of significant clusters for each dataset and miRNA target prediction tool is denoted.

Figure 4

Results: pattern correlations. Comparison of the expression pattern correlations. (A) Shown are the distributions of correlation coefficients ρ between host and target gene expression patterns (blue) of Cluster NO I and correlation coefficients ρ between the same host genes and sampled target genes (red). The medians are illustrated by blue and red lines, respectively. Δ_m_ indicates the difference between the two medians. A missing relation between host and target gene expression would result in Δ_m_ = 0. The distributions of Δ_m_ taken over all significant clusters of the three datasets are shown in the two histograms for TargetScan (B) and our consensus model (C). Missing distances of Δ_m_ = 0 in both histograms indicate that all significant clusters deviate from the null model (sampled data). Both histograms show distributions with two maxima, indicating that positive (green) and negative (orange) correlations are approximately equally distributed over all analyzed clusters.

Figure 5

Results: Functional similarity. Functional similarity of host and target gene sets as predicted by TargetScan. (A) Frequency distribution of the functional similarity score for all 75 host-target relations. For each single host gene and its set of target genes, we calculate a mean score based on the GO annotation 'biological process'. The mean functional similarity of the host gene Copz1 to its predicted targets is 2.48 (blue line). (B) Comparison of the real functional similarity score the host gene Copz1 with a null model distribution. For the null model, a random set of miRNA target genes of the same size has been chosen 1000 times and the functional similarity score has been calculated. The real score of Copz1 deviates significantly from the null model distribution, resulting in a high _Z_-score. (C) _Z_-scores for all annotated host genes. A total of 21 out of 75 host genes show _Z_-scores > 2 and thus display a significantly higher functional similarity as expected from a random sample of target genes.

Figure 6

Graph properties. Properties of the four miRNA-target bipartite graphs. (A) The relative densities, number of existing edges divided by all possible edges, in percent of the four graphs for Pictar (PT), TargetScan (TS), RNA22 (R) and consensus model (CM). (B) Log-log plot of the number of predicted miRNA targets for all four different prediction graphs. (C) Log-log plot of cluster specific miRNA target recovery for all four different prediction graphs (for details see text). (D) The mean of the numbers of predicted miRNA targets of the complete graphs (grey), and cluster-specific recovery of miRNA targets (orange): Mean of the sums of all identified targets of one host gene cluster divided by the sums of all host genes of the cluster.

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Intronic microRNAs support their host genes by mediating synergistic and antagonistic regulatory effects - PubMed (original) (raw)