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RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response

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ABSTRACT

Background: The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the β-blocker atenolol (ATE) and the β-agonist isoproterenol (ISO).

Results: Differential expression analyses revealed a large set of genes responding to ISO (n = 1770 at FDR = 0.0001) and a comparatively small one responding to ATE (n = 23 at FDR = 0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r = −0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibit coherent transcription profiles across some strains and/or treatments. Correlations between these modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality.

Conclusions: Our study provides new insights into the transcriptional response of the heart to perturbations of the β-adrenergic system, implicating several new genes that had not been associated to this system previously.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3059-6) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus

Principal component analysis of the TMM-normalized reads in the 160 samples. The loadings of the first two principal components are plotted against each other for each sample. The type of treatment is indicated by the shape of the markers (circles for CTR, triangles for ATE and squares for ISO), while the filling of the markers refers to the strains (see legend on the right). Biological replicates (same shape and filling) tend to cluster together. For any given strain the markers corresponding to CTR and ATE are usually not far apart, while those for ISO tend to be more distal with smaller loadings on both principal components. This effect is visualized by the ellipsoids, whose centers and major axes reflect the first two moments of the respective distributions (see legend on top)
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Fig1: Principal component analysis of the TMM-normalized reads in the 160 samples. The loadings of the first two principal components are plotted against each other for each sample. The type of treatment is indicated by the shape of the markers (circles for CTR, triangles for ATE and squares for ISO), while the filling of the markers refers to the strains (see legend on the right). Biological replicates (same shape and filling) tend to cluster together. For any given strain the markers corresponding to CTR and ATE are usually not far apart, while those for ISO tend to be more distal with smaller loadings on both principal components. This effect is visualized by the ellipsoids, whose centers and major axes reflect the first two moments of the respective distributions (see legend on top)

Mentions: As a second means to reveal the global structure of the expression data, we performed principal component analysis (PCA). Projection of the data onto the first two principal components reflected the aforementioned correlation structure, placing biological replicates, and to a lesser extent samples from the same strain, close to each other (Fig. 1). The PCA further showed that ISO samples tend to better segregate from the untreated controls (CTR) of the same strains than the ATE samples, revealing a stronger transcriptional response to ISO than ATE.Fig. 1


RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response
Principal component analysis of the TMM-normalized reads in the 160 samples. The loadings of the first two principal components are plotted against each other for each sample. The type of treatment is indicated by the shape of the markers (circles for CTR, triangles for ATE and squares for ISO), while the filling of the markers refers to the strains (see legend on the right). Biological replicates (same shape and filling) tend to cluster together. For any given strain the markers corresponding to CTR and ATE are usually not far apart, while those for ISO tend to be more distal with smaller loadings on both principal components. This effect is visualized by the ellipsoids, whose centers and major axes reflect the first two moments of the respective distributions (see legend on top)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015234&req=5

Fig1: Principal component analysis of the TMM-normalized reads in the 160 samples. The loadings of the first two principal components are plotted against each other for each sample. The type of treatment is indicated by the shape of the markers (circles for CTR, triangles for ATE and squares for ISO), while the filling of the markers refers to the strains (see legend on the right). Biological replicates (same shape and filling) tend to cluster together. For any given strain the markers corresponding to CTR and ATE are usually not far apart, while those for ISO tend to be more distal with smaller loadings on both principal components. This effect is visualized by the ellipsoids, whose centers and major axes reflect the first two moments of the respective distributions (see legend on top)
Mentions: As a second means to reveal the global structure of the expression data, we performed principal component analysis (PCA). Projection of the data onto the first two principal components reflected the aforementioned correlation structure, placing biological replicates, and to a lesser extent samples from the same strain, close to each other (Fig. 1). The PCA further showed that ISO samples tend to better segregate from the untreated controls (CTR) of the same strains than the ATE samples, revealing a stronger transcriptional response to ISO than ATE.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the β-blocker atenolol (ATE) and the β-agonist isoproterenol (ISO).

Results: Differential expression analyses revealed a large set of genes responding to ISO (n = 1770 at FDR = 0.0001) and a comparatively small one responding to ATE (n = 23 at FDR = 0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r = −0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibit coherent transcription profiles across some strains and/or treatments. Correlations between these modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality.

Conclusions: Our study provides new insights into the transcriptional response of the heart to perturbations of the β-adrenergic system, implicating several new genes that had not been associated to this system previously.

Electronic supplementary material: The online version of this article (doi:10.1186/s12864-016-3059-6) contains supplementary material, which is available to authorized users.

No MeSH data available.


Related in: MedlinePlus