Context-dependent Transcriptional Cofactors Regulate Specific Wnt Target Genes. Ai Tian, Hassina Benchabane, Nan Xin, Yashi Ahmed. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH.

   The Wnt/Wingless signal transduction pathway is repetitively used during metazoan development to direct an array of cellular processes such as cell proliferation, fate specification, differentiation and apoptosis. To ensure proper development, the Wnt pathway must therefore regulate distinct target genes in different developmental/cellular contexts. The collaboration of tissue-specific transcription factors is proposed to be a mechanism underlying the contextual activation of Wnt/Wingless target genes. Using a genetic screen in Drosophila for context-specific Wingless pathway components, we identified two context-specific transcriptional regulators, Earthbound1 (Ebd1) and Erect-wing (Ewg). We established that Ewg binds DNA and recruits Ebd1 to chromatin, while Ebd1 promotes the association between TCF and Arm. Using a bioinformatics approach, we identified potential Ewg target genes whose expression is misregulated in ewg mutants. Putative Ewg and Tcf binding sites in these target genes, as well as the sequences surrounding these sites, are highly conserved across Drosophila genomes. Notably, some candidate Ewg target genes are also misregulated in ebd mutants, as well as upon Wingless pathway inhibition. We moreover find that some of their putative enhancers bind Ewg directly. Analyzing how Ewg, Ebd1, Arm and TCF cooperate to activate these enhancers will shed further light on the mechanisms of context-specific regulation of target genes.