Core liver homeostatic co-expression networks are preserved but respond to perturbations in an organism- and disease-specific manner

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DOI

  • Saeed Esmaili, Tehran University of Medical Sciences, The University of Sydney
  • ,
  • Peter Langfelder, Department of Dermatology, University of California, San Diego, California; Department of Pediatrics, University of California, San Diego, California; Rady Children's Hospital, San Diego, California.
  • ,
  • T Grant Belgard, The Bioinformatics CRO
  • ,
  • Daniele Vitale, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Mahmoud Karimi Azardaryany, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Ghazal Alipour Talesh, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Mehdi Ramezani-Moghadam, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Vikki Ho, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Daniel Dvorkin, The Bioinformatics CRO
  • ,
  • Suat Dervish, Institute of Dental Research, Westmead Centre for Oral Health and Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.
  • ,
  • Brian S Gloss, Institute of Dental Research, Westmead Centre for Oral Health and Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.
  • ,
  • Henning Grønbæk
  • Christopher Liddle, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;
  • ,
  • Jacob George, Storr Liver Unit, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Westmead, Australia;

Findings about chronic complex diseases are difficult to extrapolate from animal models to humans. We reason that organs may have core network modules that are preserved between species and are predictably altered when homeostasis is disrupted. To test this idea, we perturbed hepatic homeostasis in mice by dietary challenge and compared the liver transcriptome with that in human fatty liver disease and liver cancer. Co-expression module preservation analysis pointed to alterations in immune responses and metabolism (core modules) in both human and mouse datasets. The extent of derailment in core modules was predictive of survival in the cancer genome atlas (TCGA) liver cancer dataset. We identified module eigengene quantitative trait loci (module-eQTL) for these predictive co-expression modules, targeting of which may resolve homeostatic perturbations and improve patient outcomes. The framework presented can be used to understand homeostasis at systems levels in pre-clinical models and in humans. A record of this paper's transparent peer review process is included in the supplemental information.

OriginalsprogEngelsk
TidsskriftCell Systems
Vol/bind12
Nummer5
Sider (fra-til)432-445.e7
Antal sider14
ISSN2405-4712
DOI
StatusUdgivet - maj 2021

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Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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