Relationship of disease-associated gene expression to cardiac phenotype is buffered by genetic diversity and chromatin regulation.
Expression of a cohort of disease-associated genes, some of which are active in fetal myocardium, is considered a hallmark of transcriptional change in cardiac hypertrophy models. How this transcriptome remodeling is affected by the common genetic variation present in populations is unknown. We examined the role of genetics, as well as contributions of chromatin proteins, to regulate cardiac gene expression and heart failure susceptibility. We examined gene expression in 84 genetically distinct inbred strains of control and isoproterenol-treated mice, which exhibited varying degrees of disease. Unexpectedly, fetal gene expression was not correlated with hypertrophic phenotypes. Unbiased modeling identified 74 predictors of heart mass after isoproterenol-induced stress, but these predictors did not enrich for any cardiac pathways. However, expanded analysis of fetal genes and chromatin remodelers as groups correlated significantly with individual systemic phenotypes. Yet, cardiac transcription factors and genes shown by gain-/loss-of-function studies to contribute to hypertrophic signaling did not correlate with cardiac mass or function in disease. Because the relationship between gene expression and phenotype was strain specific, we examined genetic contribution to expression. Strikingly, strains with similar transcriptomes in the basal heart did not cluster together in the isoproterenol state, providing comprehensive evidence that there are different genetic contributors to physiological and pathological gene expression. Furthermore, the divergence in transcriptome similarity versus genetic similarity between strains is organ specific and genome-wide, suggesting chromatin is a critical buffer between genetics and gene expression.
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Elaheh
E
Karbassi
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Emma
E
Monte
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Douglas J
DJ
Chapski
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Rachel
R
Lopez
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Manuel
M
Rosa Garrido
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Joseph
J
Kim
Department of Integrative Biology and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Nicholas
N
Wisniewski
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Christoph D
CD
Rau
Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California;
Jessica J
JJ
Wang
Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
James N
JN
Weiss
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Yibin
Y
Wang
Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Microbiology Immunology and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California; and.
Aldons J
AJ
Lusis
Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Medicine/Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California; Department of Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California tvondriska@mednet.ucla.edu.
Thomas M
TM
Vondriska
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D002843:Chromatin / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006321:Heart / Q000502:physiology; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D002843:Chromatin; D014157:Transcription Factors
cardiac hypertrophy; chromatin; genetic diversity; transcriptome