Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

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 m...

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Veröffentlicht in:	Nature communications Jg. 10; H. 1; S. 2760 - 14
Hauptverfasser:	Cordero, Pablo, Parikh, Victoria N., Chin, Elizabeth T., Erbilgin, Ayca, Gloudemans, Michael J., Shang, Ching, Huang, Yong, Chang, Alex C., Smith, Kevin S., Dewey, Frederick, Zaleta, Kathia, Morley, Michael, Brandimarto, Jeff, Glazer, Nicole, Waggott, Daryl, Pavlovic, Aleksandra, Zhao, Mingming, Moravec, Christine S., Tang, W. H. Wilson, Skreen, Jamie, Malloy, Christine, Hannenhalli, Sridhar, Li, Hongzhe, Ritter, Scott, Li, Mingyao, Bernstein, Daniel, Connolly, Andrew, Hakonarson, Hakon, Lusis, Aldons J., Margulies, Kenneth B., Depaoli-Roach, Anna A., Montgomery, Stephen B., Wheeler, Matthew T., Cappola, Thomas, Ashley, Euan A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 24.06.2019 Nature Publishing Group Nature Portfolio
Schlagworte:	45/23 45/91 631/114/2391 631/208/199 692/4019/592/2727 692/4019/592/75/230 Animals Benzeneacetamides Cardiomyocytes Cells, Cultured Congestive heart failure Datasets as Topic Disease Models, Animal Female Gene expression Gene Expression Profiling - methods Gene Expression Regulation Gene Knockdown Techniques Gene mapping Gene Regulatory Networks - genetics Gene sequencing Genome-Wide Association Study Genomes Genotyping Heart Heart failure Heart Failure - etiology Heart Failure - genetics Heart Failure - metabolism Heart Failure - pathology Humanities and Social Sciences Humans Male Metabolic Networks and Pathways - genetics Metabolic pathways Metabolism Mice Mice, Knockout Middle Aged multidisciplinary Myocytes, Cardiac - pathology Phosphoprotein Phosphatases - genetics Phosphoprotein Phosphatases - metabolism Pressure Primary Cell Culture Pyridines Quantitative trait loci Quantitative Trait Loci - genetics Rats Rats, Sprague-Dawley Regulators Rewiring Ribonucleic acid RNA Science Science (multidisciplinary) Sequence Analysis, RNA - methods
ISSN:	2041-1723, 2041-1723
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Zusammenfassung:	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. The genetic and pathogenetic basis of heart failure is incompletely understood. Here, the authors present a high-fidelity tissue collection from rapidly preserved failing and non-failing control hearts which are used for eQTL mapping and network analysis, resulting in the prioritization of PPP1R3A as a heart failure gene.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-019-10591-5