Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells

Tiago Faial, Andreia S Bernardo, Sasha Mendjan, Evangelia Diamanti, Daniel Ortmann, George E Gentsch, Victoria L Mascetti, Matthew W B Trotter, James C Smith, Roger A Pedersen

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

The transcription factor brachyury (T, BRA) is one of the first markers of gastrulation and lineage specification in vertebrates. Despite its wide use and importance in stem cell and developmental biology, its functional genomic targets in human cells are largely unknown. Here, we use differentiating human embryonic stem cells to study the role of BRA in activin A-induced endoderm and BMP4-induced mesoderm progenitors. We show that BRA has distinct genome-wide binding landscapes in these two cell populations, and that BRA interacts and collaborates with SMAD1 or SMAD2/3 signalling to regulate the expression of its target genes in a cell-specific manner. Importantly, by manipulating the levels of BRA in cells exposed to different signalling environments, we demonstrate that BRA is essential for mesoderm but not for endoderm formation. Together, our data illuminate the function of BRA in the context of human embryonic development and show that the regulatory role of BRA is context dependent. Our study reinforces the importance of analysing the functions of a transcription factor in different cellular and signalling environments.

Original languageEnglish
Pages (from-to)2121-35
Number of pages15
JournalDevelopment (Cambridge)
Volume142
Issue number12
DOIs
Publication statusPublished - 15 Jun 2015

Bibliographical note

© 2015. Published by The Company of Biologists Ltd.

Keywords

  • Animals
  • Bone Morphogenetic Protein 4/metabolism
  • Cell Line
  • Embryonic Stem Cells/cytology
  • Endoderm/cytology
  • Fetal Proteins/metabolism
  • Gastrulation/physiology
  • Gene Expression Regulation, Developmental
  • Humans
  • Mesoderm/cytology
  • Mice
  • Mice, Transgenic
  • Neurogenesis/physiology
  • Smad1 Protein/metabolism
  • Smad2 Protein/metabolism
  • Smad3 Protein/metabolism
  • T-Box Domain Proteins/metabolism

Fingerprint Dive into the research topics of 'Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells'. Together they form a unique fingerprint.

Cite this