Jan 28, 2016

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

BioRxiv : the Preprint Server for Biology
Pablo CorderoEuan A. Ashley

Abstract

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvested 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtained genome-wide genotyping and gene expression measurements for a subset of 313. We built failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerged as a novel regulator whose network connectivity changed significantly between health and disease. Time-course RNA sequencing after PPP1R3A knock-down validated network-based predictions of metabolic pathway expression, increased cardiomyocyte size, and perturbed respiratory metabolism. Mice lacking PPP1R3A were protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify new cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a novel central protective regulator in heart failure.

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Mentioned in this Paper

Metabolic Process, Cellular
Genome-Wide Association Study
Quantitative Trait Loci
PPP1R3A protein, human
Size
Operating Room
Sequence Determinations, RNA
SMARCA4 gene
PPP1R3A
Myl3

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