The canonical Wnt pathway fundamentally contributes to metazoan development, tissue homeostasis and human malignancies. At its core is the regulation of Wnt target gene transcription by nuclear β-catenin.
β-Catenin is one of the most prominent members of the Armadillo (ARM) repeat protein superfamily. To mediate Wnt target gene activation, the central region of the protein interacts with the DNA-binding T cell factor (TCF) family proteins that are bound to Wnt response elements (WREs), while the amino- and carboxy-terminal regions coordinate auxiliary chromatin remodelling and recognition cofactors.
The most N-terminal ARM repeat recruits BCL-9 (Legless (LGS) in Drosophila melanogaster), which in turn binds pygopus (Pygo). This interaction is required for all of the Wingless-dependent effects that have been analysed in D. melanogaster. Pygo has been implicated in the binding of modified histone H3 tails, thus linking its Wnt function with chromatin recognition.
Diverse chromatin-modifying factors are recruited by the more C-terminal region of β-catenin — the histone acetyltransferases (HATs) CBP, p300 and TIP60, the SWI/SNF factors BRG1 (Brahma (BRM) in D. melanogaster) and ISWI, the Mediator component MED12, and the polymerase-associated factor 1 (PAF1) complex protein parafibromin (Hyrax (HYX) in D. melanogaster). A simple paradigm is that the region of β-catenin from ARM repeat 11 to the C-terminal domain serves as a scaffold to orchestrate the recruitment and sequential exchange of chromatin-remodelling factors at WREs.
Is there crosstalk between the cofactors recruited to these N- and C-terminal tails of β-catenin? Several experimental readouts rely on the contribution of both sides. Furthermore, β-catenin-orchestrated chromatin remodelling could profoundly affect, and be co-dependent on, the activities of other transcription factors bound to a TCF-controlled genomic locus.
One of the key future challenges will be to elucidate how the activity of β-catenin can be curbed once it is engaged in gene activation. The known components of the nuclear Wnt signalling complex might contain an endogenous key for inactivating this process.
The canonical Wnt pathway has gathered much attention in recent years owing to its fundamental contribution to metazoan development, tissue homeostasis and human malignancies. Wnt target gene transcription is regulated by nuclear β-catenin, and genetic assays have revealed various collaborating protein cofactors. Their daunting number and diverse nature, however, make it difficult to arrange an orderly picture of the nuclear Wnt transduction events. Yet, these findings emphasize that β-catenin-mediated transcription affects chromatin. How does β-catenin cope with chromatin regulation to turn on Wnt target genes?
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We apologize to those colleagues whose work we do not directly cite owing to space limitations. We would also like to thank past and present members of the Basler laboratory for creating an environment that nurtured the ideas presented in this Review. This work was supported by the National Center of Competence in Research “Frontiers in Genetics,” the Swiss National Science Foundation, and the Kanton of Zürich.
An assembly of 146 base pairs of DNA wrapped in 2 turns around an octameric complex that is composed of the core histones H2A, H2B, H3 and H4, thus forming the basic unit of chromatin.
Describes the cooperative protein assembly that is formed at a transcription-controlling enhancer region. The enhanceosome involves gene-specific transcription factors, chromatin-remodelling factors and components of the general transcription machinery.
- MLL complex
(Mixed lineage leukaemia). A COMPASS (complex proteins associated with Set1)-like complex with histone methyltransferase activity, which is minimally composed of MLL, ASH2, menin, RBBP5, WDR5 and DPY30.
- Histone methyltransferase
An enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to Lys or Arg residues found in histones.
- PAF1 complex
(Polymerase-associated factor 1). A protein assembly that mediates histone modifications during initiation and elongation, minimally containing the factors PAF1, CTR9, LEO1, RTF1 and CDC73.
- Polytene chromosome
A large chromosome that results from the successive replication of a homologous chromosome, without ensuing separation and cell division.
- Pre-initiation complex
Formed minimally by the general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF and TFIIH, this complex positions RNA polymerase II and prepares the necessary steps required for transcriptional initiation.
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Mosimann, C., Hausmann, G. & Basler, K. β-Catenin hits chromatin: regulation of Wnt target gene activation. Nat Rev Mol Cell Biol 10, 276–286 (2009). https://doi.org/10.1038/nrm2654
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