title: The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription.
abstract: Pygopus has been discovered as a fundamental Wnt signaling component in Drosophila. The mouse genome encodes two Pygopus homologs, Pygo1 and Pygo2. They serve as context-dependent β-catenin coactivators, with Pygo2 playing the more important role. All Pygo proteins share a highly conserved plant homology domain (PHD) that allows them to bind di- and trimethylated lysine 4 of histone H3 (H3K4me2/3). Despite the structural conservation of this domain, the relevance of histone binding for the role of Pygo2 as a Wnt signaling component and as a reader of chromatin modifications remains speculative. Here we generate a knock-in mouse line, homozygous for a Pygo2 mutant defective in chromatin binding. We show that even in the absence of the potentially redundant Pygo1, Pygo2 does not require the H3K4me2/3 binding activity to sustain its function during mouse development. Indeed, during tissue homeostasis, Wnt/β-catenin-dependent transcription is largely unaffected. However, the Pygo2-chromatin interaction is relevant in testes, where, importantly, Pygo2 binds in vivo to the chromatin in a PHD-dependent manner. Its presence on regulatory regions does not affect the transcription of nearby genes; rather, it is important for the recruitment of the histone acetyltransferase Gcn5 to chromatin, consistent with a testis-specific and Wnt-unrelated role for Pygo2 as a chromatin remodeler.
authors: Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
authors: Claudio
authors: C
authors: Cantù
authors: Tomas
authors: T
authors: Valenta
authors: George
authors: G
authors: Hausmann
authors: Nathalie
authors: N
authors: Vilain
authors: Michel
authors: M
authors: Aguet
authors: Konrad
authors: K
authors: Basler
mesh_terms: D000818:Animals; D042002:Chromatin Assembly and Disassembly; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D005260:Female; D005298:Fertility; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D005838:Genotype; D006657:Histones / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054730:Protein Interaction Domains and Motifs; D013737:Testis / Q000378:metabolism; D060449:Wnt Signaling Pathway; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D029721:Drosophila Proteins; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C453400:pygo protein, Drosophila; C495570:pygopus 2 protein, mouse
keywords: Chromatin; Drosophila; Mouse; Pygopus; Transcriptional regulation; Wnt signaling