Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany.
Dev Cell. 2023 Sep 25;58(18):1627-1642.e7. doi: 10.1016/j.devcel.2023.07.023. Epub 2023 Aug 25.
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 in 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 mouse 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 coexpressing cells during early gastrulation to ensure the proper sequence of early AM and DE lineage specification followed by posterior mesoderm derivatives.
哺乳动物中中胚层和原肠胚（DE）的特化由两个相关的 T 盒转录因子（TFs）Eomesodermin（Eomes）和 Brachyury 指导，它们具有部分冗余的功能。突变胚胎表型的明显差异表明每个 TF 具有特定的功能。迄今为止，Eomes 和 Brachyury 对分离的谱系特异性基因调控的分子细节仍知之甚少。在这里，我们结合小鼠胚胎和基于干细胞的分析来描绘非重叠的、谱系特异性的转录活性。在全基因组范围内，这两个 TF 的结合在靶基因的启动子处重叠，但在远端增强子区域具有特异性，这是由 Tbx DNA 结合基序的差异赋予的。独特的结合到增强子位点上，指导了 Eomes 对前中胚层（AM）和 DE 的特化，以及 Brachyury 对尾侧中胚层的特化。值得注意的是，EOMES 在早期原肠胚形成过程中在共表达细胞中拮抗 BRACHYURY 基因调控功能，以确保随后的 AM 和 DE 谱系特化以及随后的后中胚层衍生物的正确顺序。
