Poising genes for signal-induced transcription by Pygo proteins
Pygo proteins are associated with TCF target genes that are repressed by Groucho/TLE in the absence of Wnt signalling. They thus poise these genes for Wnt-induced de-repression, facilitating access of Armadillo to TCF and overcoming their Groucho-dependent repression. Their PHD fingers bind to histone H3 tail methylated at lysine 4 and, through a different surface, to their Legless/BCL9 co-factor, which in turn binds Armadillo/eta-catenin. Intriguingly, fly Pygo orthologs exhibit a series of co-adapted mutations that reduce their histone-binding affinity, but also allow the emergence of a physiologically relevant semi-aromatic pocket that recognises asymmetrically-methylated arginine 2, a chromatin mark of repressed genes. Humanising fly Pygo restores high-affinity histone binding, creating a gain-of-function mutant of Pygo capable of de-repressing Notch target genes during fly development (which, like Wnt target genes, are repressed by Groucho/TLE). This indicates an inherent function of Pygo proteins in poising Notch target genes for de-repression which is disabled in flies (explaining why Drosophila Pygo appears dedicated to Wingless signalling). This notion of a dual function of Pygo orthologs in Wnt- and Notch-dependent transcription is supported by our discovery of a new Pygo ligand, a protein complex that recognises its N-terminal NPF motif: this complex apparently associates with TCF and Notch enhancers through Groucho/TLE, thereby poising them for signal-dependent activation (and subsequent re-repression) during fly development and in murine stem cell compartments.