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Comparative Transcriptomics Analyses in Livers of Mice, Humans, and Humanized Mice Define Human-Specific Gene

Chengfei Jiang1, Ping Li1, Xiangbo Ruan1

  • 1Cardiovascular Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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|December 3, 2020
PubMed
Summary

Differences in gene regulation between human and mouse liver cells persist even under controlled conditions. Cell-autonomous variations suggest many human genes require human or humanized systems for accurate study.

Keywords:
humanized micelivernonalcoholic fatty liver disease (NAFLD)nonalcoholic steatohepatitis (NASH)

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Area of Science:

  • Biomedical research
  • Comparative genomics
  • Translational medicine

Background:

  • Mouse models are crucial but show significant gene regulation differences compared to humans.
  • Understanding these differences is key for accurate translation of research findings.

Purpose of the Study:

  • To investigate whether environmental factors or cell-autonomous differences cause divergent gene regulation between human and mouse liver cells.
  • To determine if human genes require human-specific systems for study.

Main Methods:

  • Stepwise comparative analyses of gene regulation in human, mouse, and humanized livers.
  • Bioinformatics approaches to analyze gene networks and biological processes.
  • Controlled comparisons minimizing genetic, gender, and environmental biases.

Main Results:

  • Over 50% of commonly regulated genes showed opposite regulation in human and mouse livers, even under minimized bias.
  • This pattern of opposite regulation persisted in humanized mouse models.
  • Gene network analyses revealed substantial differences in biological processes and identified conserved lncRNAs.

Conclusions:

  • Cell-autonomous differences significantly contribute to divergent gene regulation between human and mouse livers.
  • A notable number of biological processes are human-specifically regulated.
  • Mouse models may not fully recapitulate human liver gene regulation, necessitating human or humanized systems.