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Disentangling cell-intrinsic and cell-extrinsic factors underlying evolution.

Alexander L Starr1, Toshiya Nishimura2, Kyomi J Igarashi3

  • 1Department of Biology, Stanford University, Stanford, CA 94305, USA.

Cell Genomics
|May 30, 2025
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Summary
This summary is machine-generated.

Cells mostly function autonomously, but environmental interactions are crucial. Interspecies chimeras reveal cell-intrinsic factors drive most evolutionary divergence, with extrinsic factors playing a key role in gene regulation.

Keywords:
autonomouschimeradevelopmentevolutionextrinsicgene expressionimprintingintrinsicmouserat

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Area of Science:

  • Evolutionary biology
  • Cell biology
  • Genomics

Background:

  • Understanding cellular function requires distinguishing cell-intrinsic autonomy from cell-extrinsic interactions.
  • Evolutionary divergence of cellular traits is complex, involving both internal cellular mechanisms and external environmental influences.

Purpose of the Study:

  • To develop a novel framework using interspecies chimeras to dissect cellular trait evolution into cell-intrinsic and cell-extrinsic components.
  • To investigate the relative contributions of intrinsic and extrinsic factors to gene expression divergence.

Main Methods:

  • Development of a conceptual framework for analyzing interspecies chimeras.
  • Application of the framework to analyze thousands of gene expression levels in reciprocal rat-mouse chimeras.
  • Analysis of imprinted gene expression in chimeric models.

Main Results:

  • The majority of evolutionary divergence in gene expression is cell-intrinsic.
  • Cell-extrinsic factors significantly influence gene regulation, impacting transcription factors and their downstream targets at both mRNA and protein levels.
  • Imprinted genes exhibit substantial misexpression in chimeras, indicating a conflict between evolving intrinsic and extrinsic imprinting mechanisms.

Conclusions:

  • The developed chimera-based framework effectively decomposes cellular trait evolution into intrinsic and extrinsic components.
  • Cell-intrinsic factors are the primary drivers of evolutionary divergence, but cell-extrinsic factors are integral to gene regulation.
  • Rapid evolution of imprinting mechanisms may lead to incompatibilities in interspecies chimeras, offering insights into developmental regulation.