西亚试剂：Genome-Wide Identification of Smad/Foxh1 Targets Reveals a

Genome-Wide Identification of Smad/Foxh1 Targets Reveals a Role for Foxh1 in Retinoic Acid Regulation and Forebrain Development
Cristoforo Silvestri,1,5 Masahiro Narimatsu,6 Ingo von Both,6 Yongmei Liu,6 Nicholas B.J. Tan,2 Luisa Izzi,3,5 Peter McCaffery,7 Jeffrey L. Wrana,4,6 and Liliana Attisano1,2,3,5,

1 Institute of Medical Science, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
2 Department of Biochemistry, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
3 Department of Medical Biophysics, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
4 Department of Medical Genetics and Microbiology, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
5 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, Ontario M5S 3E1, Canada
6 Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada
7 Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom

Corresponding author
Liliana Attisano

Summary

Foxh1, a Smad DNA-binding partner, mediates TGFβ-dependent gene expression during early development. Few Foxh1 targets are known. Here, we describe a genome-wide approach that we developed that couples systematic mapping of a functional Smad/Foxh1 enhancer (SFE) to Site Search, a program used to search annotated genomes for composite response elements. Ranking of SFEs that are positionally conserved across species yielded a set of genes enriched in Foxh1 targets. Analysis of top candidates, such as Hesx1, Lgr4, Lmo1, Fgf8, and members of the Aldh1a subfamily, revealed that Foxh1 initiates a transcriptional regulatory network within the developing anterior neuroectoderm. The Aldh1a family is required for retinoic acid (RA) synthesis, and, in Foxh1 mutants, expression of Aldh1a1, -2, and -3 and activation of a RA-responsive transgenic reporter is abolished in anterior structures. Integrated mapping of a developmental transcription factor network thus reveals a key role for Foxh1 in patterning and initiating RA signaling in the forebrain.

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