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

Pablo Cordero, Victoria N. Parikh, Elizabeth T. Chin, Ayca Erbilgin, Michael J. Gloudemans, Ching Shang, Yong Huang, Alex C. Chang, Kevin S. Smith, Frederick Dewey, Kathia Zaleta, Michael Morley, Jeff Brandimarto, Nicole Glazer, Daryl Waggott, Aleksandra Pavlovic, Mingming Zhao, Christine S. Moravec, W. H. Wilson Tang, Jamie Skreen, Christine Malloy, Sridhar Hannenhalli, Hongzhe Li, Scott Ritter, Mingyao Li, Daniel Bernstein, Andrew Connolly, Hakon Hakonarson, Aldons J. Lusis, Kenneth B. Margulies, Anna A. Depaoli-Roach, Stephen B. Montgomery, Matthew T. Wheeler, Thomas Cappola and Euan A. Ashley ()
Additional contact information
Pablo Cordero: Stanford University
Victoria N. Parikh: Stanford University
Elizabeth T. Chin: Stanford University
Ayca Erbilgin: Stanford University
Michael J. Gloudemans: Stanford University
Ching Shang: Stanford University
Yong Huang: Stanford University
Alex C. Chang: Stanford University
Kevin S. Smith: Stanford University
Frederick Dewey: Stanford University
Kathia Zaleta: Stanford University
Michael Morley: University of Pennsylvania
Jeff Brandimarto: University of Pennsylvania
Nicole Glazer: Boston University School of Medicine
Daryl Waggott: Stanford University
Aleksandra Pavlovic: Stanford University
Mingming Zhao: Stanford University
Christine S. Moravec: Lerner Research Institute
W. H. Wilson Tang: Lerner Research Institute
Jamie Skreen: Providence Medical Group—Milwaukie
Christine Malloy: University of Maryland
Sridhar Hannenhalli: University of Maryland
Hongzhe Li: University of Pennsylvania
Scott Ritter: University of Pennsylvania
Mingyao Li: University of Pennsylvania
Daniel Bernstein: Stanford University
Andrew Connolly: University of California San Francisco
Hakon Hakonarson: The Children’s Hospital of Philadelphia
Aldons J. Lusis: University of California Los Angeles
Kenneth B. Margulies: University of Pennsylvania
Anna A. Depaoli-Roach: Indiana University
Stephen B. Montgomery: Stanford University
Matthew T. Wheeler: Stanford University
Thomas Cappola: University of Pennsylvania
Euan A. Ashley: Stanford University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10591-5

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