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Charting Brachyury-mediated developmental pathways during early mouse embryogenesis.

Macarena Lolas1, Pablo D T Valenzuela, Robert Tjian

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This study maps the Brachyury gene network, revealing its role as a transcriptional activator in early development. It highlights Brachyury

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Area of Science:

  • Developmental Biology
  • Genetics
  • Molecular Biology

Background:

  • Early embryogenesis involves complex lineage specification and morphogenetic processes.
  • Brachyury is a key developmental regulator with a poorly understood genome-wide function.

Purpose of the Study:

  • To systematically identify transcriptional programs regulated by Brachyury.
  • To elucidate the Brachyury-dependent gene regulatory network and its role in development.

Main Methods:

  • Chromosomal localization mapping using ChIP sequencing and ChIP-exonuclease.
  • Genome-wide in vitro and in vivo perturbation analysis.
  • Cross-species evolutionary comparison and mRNA-sequencing correlation analysis.

Main Results:

  • Identified Brachyury-bound enhancers with distinct sequence signatures.
  • Unveiled a detailed Brachyury-dependent gene-regulatory network.
  • Demonstrated Brachyury functions primarily as a transcriptional activator, including a feedback loop with Foxa2 and Sox17 for stem cell commitment.

Conclusions:

  • Brachyury directly influences diverse developmental pathways and cellular housekeeping programs.
  • The Brachyury-Foxa2-Sox17 feedback loop is critical for stem cell lineage commitment.
  • Brachyury is crucial for up-regulating hematopoietic and muscle-fate regulators, ensuring developmental homeostasis.