title: Charting Brachyury-mediated developmental pathways during early mouse embryogenesis.
abstract: To gain insights into coordinated lineage-specification and morphogenetic processes during early embryogenesis, here we report a systematic identification of transcriptional programs mediated by a key developmental regulator--Brachyury. High-resolution chromosomal localization mapping of Brachyury by ChIP sequencing and ChIP-exonuclease revealed distinct sequence signatures enriched in Brachyury-bound enhancers. A combination of genome-wide in vitro and in vivo perturbation analysis and cross-species evolutionary comparison unveiled a detailed Brachyury-dependent gene-regulatory network that directly links the function of Brachyury to diverse developmental pathways and cellular housekeeping programs. We also show that Brachyury functions primarily as a transcriptional activator genome-wide and that an unexpected gene-regulatory feedback loop consisting of Brachyury, Foxa2, and Sox17 directs proper stem-cell lineage commitment during streak formation. Target gene and mRNA-sequencing correlation analysis of the T(c) mouse model supports a crucial role of Brachyury in up-regulating multiple key hematopoietic and muscle-fate regulators. Our results thus chart a comprehensive map of the Brachyury-mediated gene-regulatory network and how it influences in vivo developmental homeostasis and coordination.
authors.affiliation: Junior Fellow Program, Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147.
authors.forename: Macarena
authors.initials: M
authors.lastname: Lolas
authors.forename: Pablo D T
authors.initials: PD
authors.lastname: Valenzuela
authors.forename: Robert
authors.initials: R
authors.lastname: Tjian
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D047108:Embryonic Development / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D005326:Fetal Proteins / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D020825:T-Box Domain Proteins / Q000502:physiology*; D000098908:Brachyury Protein
chemical_list: D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein
keywords: early development; mesoendoderm differentiation; primitive streak