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



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.



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.
Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Andrea
A
Prunotto
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Brian J
BJ
Stevenson
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.
Corinne
C
Berthonneche
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.
Fanny
F
Schüpfer
Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland.
Jacques S
JS
Beckmann
Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland. Fabienne.Maurer@chuv.ch.
Fabienne
F
Maurer
Department of Medical Genetics, University of Lausanne, Rue du Bugnon 27, 1011, Lausanne, Switzerland. Sven.Bergmann@unil.ch.|Swiss Institute of Bioinformatics, Lausanne, Switzerland. Sven.Bergmann@unil.ch.|Department of Integrative Biomedical Sciences, University of Cape Town, Cape Town, South Africa. Sven.Bergmann@unil.ch.
Sven
0000-0002-6785-9034
S
Bergmann
D000818:Animals; D001262:Atenolol / Q000494:pharmacology*; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation / Q000187:drug effects; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects*; D006321:Heart / Q000187:drug effects*; D007545:Isoproterenol / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D017423:Sequence Analysis, RNA / Q000379:methods*; D012984:Software
D001262:Atenolol; D007545:Isoproterenol
Atenolol; Cardiac hypertrophy; Isoproterenol; Mouse heart; RNAseq; β-adrenergic system