10779/crick.12681905.v1
Tiago Faial
Tiago
Faial
Andreia S Bernardo
Andreia S
Bernardo
Sasha Mendjan
Sasha
Mendjan
Evangelia Diamanti
Evangelia
Diamanti
Daniel Ortmann
Daniel
Ortmann
George E Gentsch
George E
Gentsch
Victoria L Mascetti
Victoria L
Mascetti
Matthew WB Trotter
Matthew WB
Trotter
James C Smith
James C
Smith
Roger A Pedersen
Roger A
Pedersen
Brachyury and SMAD signalling collaboratively orchestrate distinct mesoderm and endoderm gene regulatory networks in differentiating human embryonic stem cells
The Francis Crick Institute
2020
Embryonic stem cells
Gastrulation
Gene regulatory networks
Human
SMAD
T-BOX
Animals
Bone Morphogenetic Protein 4
Cell Line
Embryonic Stem Cells
Endoderm
Fetal Proteins
Gene Expression Regulation, Developmental
Humans
Mesoderm
Mice
Mice, Transgenic
Neurogenesis
Smad1 Protein
Smad2 Protein
Smad3 Protein
T-Box Domain Proteins
Smith U117597140
AS-ack
06 Biological Sciences
11 Medical and Health Sciences
2020-07-21 11:31:05
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Brachyury_and_SMAD_signalling_collaboratively_orchestrate_distinct_mesoderm_and_endoderm_gene_regulatory_networks_in_differentiating_human_embryonic_stem_cells/12681905
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.