1. Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure.
- Author
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Cordero P, Parikh VN, Chin ET, Erbilgin A, Gloudemans MJ, Shang C, Huang Y, Chang AC, Smith KS, Dewey F, Zaleta K, Morley M, Brandimarto J, Glazer N, Waggott D, Pavlovic A, Zhao M, Moravec CS, Tang WHW, Skreen J, Malloy C, Hannenhalli S, Li H, Ritter S, Li M, Bernstein D, Connolly A, Hakonarson H, Lusis AJ, Margulies KB, Depaoli-Roach AA, Montgomery SB, Wheeler MT, Cappola T, and Ashley EA
- Subjects
- Animals, Benzeneacetamides, Cells, Cultured, Datasets as Topic, Disease Models, Animal, Female, Gene Expression Profiling methods, Gene Expression Regulation, Gene Knockdown Techniques, Genome-Wide Association Study, Heart Failure etiology, Heart Failure metabolism, Heart Failure pathology, Humans, Male, Metabolic Networks and Pathways genetics, Mice, Mice, Knockout, Middle Aged, Phosphoprotein Phosphatases genetics, Primary Cell Culture, Pyridines, Quantitative Trait Loci genetics, Rats, Rats, Sprague-Dawley, Sequence Analysis, RNA methods, Gene Regulatory Networks genetics, Heart Failure genetics, Myocytes, Cardiac pathology, Phosphoprotein Phosphatases metabolism
- Abstract
Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.
- Published
- 2019
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