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PLoS One January 1, 2012; 7 (3): e33346.

Genomic targets of Brachyury (T) in differentiating mouse embryonic stem cells.

Evans AL , Faial T , Gilchrist MJ , Down T , Vallier L , Pedersen RA , Wardle FC , Smith JC .

BACKGROUND: The T-box transcription factor Brachyury (T) is essential for formation of the posterior mesoderm and the notochord in vertebrate embryos. Work in the frog and the zebrafish has identified some direct genomic targets of Brachyury, but little is known about Brachyury targets in the mouse. METHODOLOGY/PRINCIPAL FINDINGS: Here we use chromatin immunoprecipitation and mouse promoter microarrays to identify targets of Brachyury in embryoid bodies formed from differentiating mouse ES cells. The targets we identify are enriched for sequence-specific DNA binding proteins and include components of signal transduction pathways that direct cell fate in the primitive streak and tailbud of the early embryo. Expression of some of these targets, such as Axin2, Fgf8 and Wnt3a, is down regulated in Brachyury mutant embryos and we demonstrate that they are also Brachyury targets in the human. Surprisingly, we do not observe enrichment of the canonical T-domain DNA binding sequence 5''-TCACACCT-3'' in the vicinity of most Brachyury target genes. Rather, we have identified an (AC)(n) repeat sequence, which is conserved in the rat but not in human, zebrafish or Xenopus. We do not understand the significance of this sequence, but speculate that it enhances transcription factor binding in the regulatory regions of Brachyury target genes in rodents. CONCLUSIONS/SIGNIFICANCE: Our work identifies the genomic targets of a key regulator of mesoderm formation in the early mouse embryo, thereby providing insights into the Brachyury-driven genetic regulatory network and allowing us to compare the function of Brachyury in different species.

PubMed ID: 22479388
PMC ID: PMC3316570
Article link: PLoS One
Grant support: [+]

Species referenced: Xenopus
Genes referenced: actb actl6a axin2 ctnnb1 dkk1 dvl3 epha8 fgf8 foxa2 foxe1 jup ncapd2 tbxt tubb2b wnt3a

Article Images: [+] show captions
References [+] :
Anderson, The onset of germ cell migration in the mouse embryo. 2000, Pubmed