EomesrestrictsBrachyuryfunctions at the onset of mammalian gastrulation
Abstract
Mammalian specification of mesoderm and definitive endoderm (DE) is instructed by the two related Tbx transcription factors (TFs) Eomesodermin ( Eomes ) and Brachyury sharing partially redundant functions. Gross differences of mutant embryonic phenotypes suggest specific functions of each TF. To date, the molecular details of separated lineage-specific gene-regulation by Eomes and Brachyury remain poorly understood. Here, we combine embryonic and stem cell-based analyses to delineate the non-overlapping, lineage-specific transcriptional activities. On a genome-wide scale binding of both TFs overlaps at promoters of target genes, but shows specificity for distal enhancer regions, that is conferred by differences in Tbx DNA-binding motifs. The unique binding to enhancer sites instructs the specification of anterior mesoderm (AM) and DE by Eomes and caudal mesoderm by Brachyury . Remarkably, EOMES antagonizes BRACHYURY gene-regulatory functions in co-expressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives.