Genomic integration of Wnt/{beta}-catenin and BMP/Smad1 signaling coordinates foregut and hindgut transcriptional program [RESEARCH ARTICLE]

Mariana L. Stevens, Praneet Chaturvedi, Scott A. Rankin, Melissa Macdonald, Sajjeev Jagannathan, Masashi Yukawa, Artem Barski, and Aaron M. Zorn

Digestive system development is orchestrated by combinatorial signaling interactions between endoderm and mesoderm, but how these signals are integrated in the genome is poorly understood. Here we identified the transcriptomes of Xenopus foregut 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-BMP signaling was mediated by Smad1 and β-catenin co-occupying hundreds of DNA cis-regulatory elements, and by a crosstalk where Wnt negatively regulated BMP ligand expression in the foregut. These results extend our understanding of gastrointestinal organogenesis and how Wnt and BMP may coordinate genomic responses in other contexts.

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