Decoding of Methylated Histone H3 Tail by the Pygo-BCL9 Wnt Signaling Complex

Abstract

SummaryPygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of β-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.

Wnt Signaling from Development to Disease: Insights from Model Systems

“…In addition, Pygo's PHD domain can bind histone H3 methylated at lysine 4 (H3K4me). This is dependent on Lgs and is important for Pygo function in vivo (Fiedler et al 2008). …”

“…However, even though Pygo's biochemical properties are conserved in mammalian Pygo1 and Pygo2 (Fiedler et al 2008;Kramps et al 2002), pygo1, pygo2 or double knockouts in mice have a surprisingly mild decrease in Wnt signaling (Li et al 2007a;Schwab et al 2007;Song et al 2007). Perhaps this is because mouse BCL9 contains its own transactivation domain (Sustmann et al 2008).…”

Epigenetic regulation of aging stem cells

“…The role of b-catenin in adult stem cell function may be mediated through its activity at chromatin, as b-catenin complexes with chromatin remodelers such as SMARCA4/BRG1 (Barker et al, 2001;Major et al, 2008) and HATs such as CBP (Hecht et al, 2000). In addition, the roles for transcriptional cofactors of b-catenin, BCL9/BCL9L and PYGO2, in adult stem cell proliferation have been associated with their function as readers of histone marks H3K4me2 and H3K4me3 (Fiedler et al, 2008;Chen et al, 2010). BCL9 and homolog BCL9L are necessary for adult stem cellmediated regeneration of muscle and colon epithelium (Brack et al, 2009;Deka et al, 2010), whereas PYGO2 promotes self-renewal of mammary progenitor cells through regulation of cell cycle progression (Gu et al, 2009;Chen et al, 2010).…”

Pygo2 regulates β-catenin–induced activation of hair follicle stem/progenitor cells and skin hyperplasia

“…Pygo proteins directly bind to an active transcriptional histone mark, lysine 4-trimethylated histone H3 (H3K4me3) (14,15). Furthermore, Pygo2 regulates the production of histone marks at target loci in part by recruiting histone-modifying enzymes (15)(16)(17)(18)(19)(20).…”