Pygopus and the Wnt signaling pathway: A diverse set of connections

Jessen, Shannon; Gu, Bingnan; Dai, Xing

doi:10.1002/bies.20757

Cited by 57 publications

(50 citation statements)

References 78 publications

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“…Rather, the consequences of abrogating the interaction are restricted to a late step in spermiogenesis. In an expanding number of contexts in which Pygo2 is being implicated as a modulator of Wnt signaling (Mosimann et al, 2009;Jessen et al, 2008;Chen et al, 2010), our work provides an important piece of the puzzle needed for a holistic understanding. .…”

Section: Research Articlementioning

confidence: 99%

The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription

et al. 2013

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SUMMARYPygopus 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.

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Section: Research Articlementioning

confidence: 99%

The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription

et al. 2013

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“…The Wnt/b-catenin transcription complex component, Pygopus, was originally identified as a protein required for Wnt-dependent transcriptional activation during embryonic development (1). Pygopus is also overexpressed in and is required for the growth of a number of cancer cell lines of diverse origin (2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Human Papilloma Virus (HPV) E7-Mediated Attenuation of Retinoblastoma (Rb) Induces hPygopus2 Expression via Elf-1 in Cervical Cancer

Tzenov

Andrews

Voisey

et al. 2013

Molecular Cancer Research

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The human papillomavirus (HPV) is the etiologic agent of cervical cancer. In this study, we provide evidence for the human Pygopus (hPygo)2 gene as a cellular biomarker for HPV-related disease. In a tumor microarray of cervical cancer progression, hPygo2 levels were greater in high-grade lesions and squamous cell carcinomas than in normal epithelia. Similarly, hPygo2 mRNA and protein levels were greater in HPV-positive cervical cancer cells relative to uninfected primary cells. RNA interference (RNAi)-mediated depletion of HPV-E7 increased whereas E74-like factor (Elf)-1 RNAi decreased association of Retinoblastoma (Rb) tumor suppressor with the hPygo2 promoter in cervical cancer cell lines. Transfection of dominant-active Rb inhibited Elf-1-dependent activation of hPygo2, whereas Elf-1 itself increased hPygo2 expression. Chromatin immunoprecipitation assays showed that Rb repressed hPygo2 by inhibiting Elf-1 at the Ets-binding site in the hPygo2 promoter. These results suggested that abrogation of Rb by E7 resulted in derepression of Elf-1, which in turn stimulated expression of hPygo2.

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“…The Pygopus (Pygo) family of proteins regulates Wnt/β-catenin signaling by controlling transcription (13) as well as linking this pathway to changes in epigenetic chromatin marks. Pygo proteins directly bind to an active transcriptional histone mark, lysine 4-trimethylated histone H3 (H3K4me3) (14,15).…”

mentioning

confidence: 99%

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

Sun

Watanabe

Fallahi

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the epigenetic mechanisms that control the activation of adult stem cells holds the promise of tissue and organ regeneration. Hair follicle stem cells have emerged as a prime model to study stem cell activation. Wnt/β-catenin signaling controls multiple aspects of skin epithelial regeneration, with its excessive activity promoting the hyperactivation of hair follicle stem/ progenitor cells and tumorigenesis. The contribution of chromatin factors in regulating Wnt/β-catenin pathway function in these processes is unknown. Here, we show that chromatin effector Pygopus homolog 2 (Pygo2) produced by the epithelial cells facilitates depilation-induced hair regeneration, as well as β-catenin-induced activation of hair follicle stem/early progenitor cells and trichofolliculoma-like skin hyperplasia. Pygo2 maximizes the expression of Wnt/β-catenin targets, but is dispensable for β-catenin-mediated expansion of LIM/homeobox protein Lhx2 + cells, in the stem/early progenitor cell compartment of the hair follicle. Moreover, β-catenin and Pygo2 converge to induce the accumulation and acetylation of tumor suppressor protein p53 upon the cell cycle entry of hair follicle early progenitor cells and in cultured keratinocytes. These findings identify Pygo2 as an important regulator of Wnt/ β-catenin function in skin epithelia and p53 activation as a prominent downstream event of β-catenin/Pygo2 action in stem cell activation.

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Pygopus and the Wnt signaling pathway: A diverse set of connections

Cited by 57 publications

References 78 publications

The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription

The Pygo2-H3K4me2/3 interaction is dispensable for mouse development and Wnt signaling-dependent transcription

Human Papilloma Virus (HPV) E7-Mediated Attenuation of Retinoblastoma (Rb) Induces hPygopus2 Expression via Elf-1 in Cervical Cancer

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

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