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 SkreenChristine 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, Euan A. Ashley

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article number2760
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Cordero, P., Parikh, V. N., Chin, E. T., Erbilgin, A., Gloudemans, M. J., Shang, C., Huang, Y., Chang, A. C., Smith, K. S., Dewey, F., Zaleta, K., Morley, M., Brandimarto, J., Glazer, N., Waggott, D., Pavlovic, A., Zhao, M., Moravec, C. S., Tang, W. H. W., ... Ashley, E. A. (2019). Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure. Nature communications, 10(1), [2760]. https://doi.org/10.1038/s41467-019-10591-5