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 & 15 others Christine Malloy, Sridhar Hannenhalli, Hongzhe Li, Scott Ritter, Mingyao Li, Daniel Bernstein, Andrew Connolly, Hakon Hakonarson, Aldons J. Lusis, Kenneth B. Margulies, Anna De Paoli-Roach, Stephen B. Montgomery, Matthew T. Wheeler, Thomas Cappola, Euan A. Ashley

Research output: Contribution to journalArticle

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
Externally publishedYes

Fingerprint

Gene Regulatory Networks
regulators
genes
Heart Failure
Genes
Pressure
Quantitative Trait Loci
loci
RNA Sequence Analysis
Operating Rooms
Operating rooms
Metabolic Networks and Pathways
Transplants
Cardiac Myocytes
sequencing
genome
mortality
gene expression
metabolism
Metabolism

ASJC Scopus subject areas

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

Cite this

Cordero, P., Parikh, V. N., Chin, E. T., Erbilgin, A., Gloudemans, M. J., Shang, C., ... 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

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure. / 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.; De Paoli-Roach, Anna; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.

In: Nature communications, Vol. 10, No. 1, 2760, 01.12.2019.

Research output: Contribution to journalArticle

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, De Paoli-Roach, A, Montgomery, SB, Wheeler, MT, Cappola, T & Ashley, EA 2019, 'Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure', Nature communications, vol. 10, no. 1, 2760. https://doi.org/10.1038/s41467-019-10591-5
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. ; De Paoli-Roach, Anna ; Montgomery, Stephen B. ; Wheeler, Matthew T. ; Cappola, Thomas ; Ashley, Euan A. / Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure. In: Nature communications. 2019 ; Vol. 10, No. 1.
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