Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure.
Nat Commun
; 10(1): 2760, 2019 06 24.
Article
em En
| MEDLINE
| ID: mdl-31235787
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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fosfoproteínas Fosfatases
/
Miócitos Cardíacos
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Redes Reguladoras de Genes
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Insuficiência Cardíaca
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos