Abstract
BackgroundThe 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).ResultsDifferential 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.ConclusionsOur 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 materialThe online version of this article (doi:10.1186/s12864-016-3059-6) contains supplementary material, which is available to authorized users.
Highlights
The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood
2; GEO, Gene expression omnibus; Gene Ontology (GO), Gene ontology; Genetic reference populations (GRPs), Genetic reference population; genome-wide association studies (GWASs), Genome-wide association study; hybrid mouse diversity panel (HMDP), Hybrid mouse diversity panel; heart rate (HR), Heart rate; ISA, Iterative signature algorithm; ISO, Isoproterenol; KEGG, Kyoto encyclopedia of genes and genomes; Lims1, LIM zinc finger domain containing 1; Molecular Function (MF), Molecular function; MGI, Mouse genome informatics; MHC, Major histocompatibility complex; Myom2, Myomesin 2; phosphate buffered saline (PBS), Phosphate buffered saline; principal component analysis (PCA), Principal component analysis; Phkg1, Phosphorylase kinase gamma subunit 1; PKA, Protein kinase A; Polr1e, Polymerase (RNA) I subunit E; PPAR, Peroxisome proliferator-activated receptor; QTc, Corrected QT interval, as recorded by ECG; RNAseq, RNA sequencing; Ryr2, Ryanodine receptor 2; SD, Standard deviation; StrainSpecificity Index (SSI), Strain-specific index; Synpo2l, Synaptopodin 2 like; TC, Tailcuff; TG, Transforming growth factor; trimmed mean of Mvalues (TMM), Trimmed mean of M-values
After filtering out 2896 genes with inconsistent evidence of expression, read counts of the remaining 16397 genes were normalized with the trimmed mean of Mvalues (TMM) method [19]
Summary
The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. 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). A range of β-blocking drugs, such as the β1-selective antagonist atenolol (ATE), have been developed to counter these effects. In the clinic, they are routinely prescribed for the management of heart failure, myocardial infarction, angina, atrial fibrillation and hypertension [8]. Longterm exposure of cellular or animal models to β-agonists such as the non-selective activator isoproterenol (ISO) can be used in the laboratory to mimic and study cardiac hypertrophy, independently of hypertension [9]
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