title: Genomic integration of Wnt/β-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional programs.
abstract: Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are interpreted in the genome is poorly understood. Here we identified the transcriptomes ofXenopusforegut and hindgut progenitors, which are conserved with mammals. Using RNA-seq and ChIP-seq we show that BMP/Smad1 regulates dorsal-ventral gene expression in both the endoderm and mesoderm, whereas Wnt/β-catenin acts as a genome-wide toggle between foregut and hindgut programs. Unexpectedly, β-catenin and Smad1 binding were associated with both transcriptional activation and repression, with Wnt-repressed genes often lacking canonical Tcf DNA binding motifs, suggesting a novel mode of direct repression. Combinatorial Wnt and BMP signaling was mediated by Smad1 and β-catenin co-occupying hundreds of cis-regulatory DNA elements, and by a crosstalk whereby Wnt negatively regulates BMP ligand expression in the foregut. These results extend our understanding of gastrointestinal organogenesis and of how Wnt and BMP might coordinate genomic responses in other contexts.
authors.affiliation: Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Mariana L
authors.initials: ML
authors.lastname: Stevens
authors.affiliation: Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Praneet
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rankin
authors.affiliation: Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Macdonald
authors.affiliation: Division of Allergy & Immunology and Human Genetics, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Sajjeev
authors.initials: S
authors.lastname: Jagannathan
authors.affiliation: Division of Allergy & Immunology and Human Genetics, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Yukawa
authors.affiliation: Division of Allergy & Immunology and Human Genetics, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Artem
authors.initials: A
authors.lastname: Barski
authors.affiliation: Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Research Foundation and Department of Pediatrics College of Medicine, University of Cincinnati, Cincinnati, OH 45229, USA aaron.zorn@cchmc.org.
authors.forename: Aaron M
authors.identifier: 0000-0003-3217-3590
authors.initials: AM
authors.lastname: Zorn
mesh_terms: D000818:Animals; D001483:Base Sequence; D019521:Body Patterning / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D004064:Digestive System / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D016678:Genome; D011485:Protein Binding; D051898:Smad1 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D059467:Transcriptome / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D019485:Bone Morphogenetic Proteins; D002843:Chromatin; D051898:Smad1 Protein; D051176:beta Catenin
keywords: BMP; ChIP-seq; Endoderm; Foregut; Hindgut; Mesoderm; RNA-seq; Smad1; Wnt; Xenopus; β-Catenin