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  • 1.
    Suzuki, Toshiyasu
    et al.
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Kilbey, Anna
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Casa-Rodriguez, Nuria
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Lawlor, Amy
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Georgakopoulou, Anastasia
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Hayman, Hannah
    Univ Glasgow, Scotland.
    Swe, Kyi Lai Yin
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Vantourout, Pierre
    Kings Coll London, England; Francis Crick Inst, England.
    Ridgway, Rachel A.
    Canc Res UK Beatson Inst, Scotland.
    Byrne, Ryan M.
    Queens Univ, North Ireland.
    Chen, Lei
    Rutgers State Univ, NJ USA.
    Verzi, Michael P.
    Rutgers State Univ, NJ USA.
    Gay, David M.
    Canc Res UK Beatson Inst, Scotland.
    Vazquez, Ester Gil
    Univ Oxford, England.
    Belnoue-Davis, Hayley L.
    Univ Oxford, England.
    Gilroy, Kathryn
    Canc Res UK Beatson Inst, Scotland.
    Kostner, Anne Helene
    Southern Hosp Trust, Norway.
    Kersten, Christian
    Southern Hosp Trust, Norway; Akershus Univ Hosp, Norway.
    Thuwajit, Chanitra
    Mahidol Univ, Thailand.
    Andersen, Ditte K.
    BioClavis Ltd, Scotland.
    Wiesheu, Robert
    Univ Glasgow, Scotland.
    Jandke, Anett
    Francis Crick Inst, England.
    Blyth, Karen
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Roseweir, Antonia K.
    Univ Glasgow, Scotland.
    Leedham, Simon J.
    Univ Oxford, England.
    Dunne, Philip D.
    Canc Res UK Beatson Inst, Scotland; Queens Univ, North Ireland.
    Edwards, Joanne
    Univ Glasgow, Scotland.
    Hayday, Adrian
    Kings Coll London, England; Francis Crick Inst, England.
    Sansom, Owen J.
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland.
    Coffelt, Seth B.
    Canc Res UK Beatson Inst, Scotland; Univ Glasgow, Scotland; Canc Res UK Beatson Inst, Scotland.
    b-Catenin Drives Butyrophilin-like Molecule Loss and gd T-cell Exclusion in Colon Cancer2023In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 11, no 8, p. 1137-1155Article in journal (Refereed)
    Abstract [en]

    Intraepithelial lymphocytes (IEL) expressing y8 T-cell receptors (y8TCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immu-nosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic y8IELs. In contrast with healthy intestinal or colonic tissue, we found that y8IELs were largely absent from the micro-environment of both mouse and human tumors, and that butyr-ophilin-like (BTNL) molecules, which can critically regulate y8IEL through direct y8TCR interactions, were also downregulated in tumors. We then demonstrated that 13-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased y8IEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of 13-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant 13-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and y8 T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts y8IEL immunosurveillance and furthers cancer progression.

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  • 2.
    Söderholm, Simon
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Jauregi Miguel, Amaia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Pagella, Pierfrancesco
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Ghezzi, Valeria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Zambanini, Gianluca
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Single-cell response to Wnt signaling activation reveals uncoupling of Wnt target gene expression2023In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 429, no 2, article id 113646Article in journal (Refereed)
    Abstract [en]

    Wnt signaling drives nuclear translocation of beta-catenin and its subsequent association with the DNA-bound TCF/LEF transcription factors, which dictate target gene specificity by recognizing Wnt responsive elements across the genome. beta-Catenin target genes are therefore thought to be collectively activated upon Wnt pathway stimulation. However, this appears in contrast with the non-overlapping patterns of Wnt target gene expression in several contexts, including early mammalian embryogenesis. Here we followed Wnt target gene expression in human embryonic stem cells after Wnt pathway stimulation at a single-cell resolution. Cells changed gene expression program over time consistent with three key developmental events: i) loss of pluripotency, ii) induction of Wnt target genes, and iii) mesoderm specification. Contrary to our expectation, not all cells displayed equal amplitude of Wnt target gene activation; rather, they distributed in a continuum from strong to weak responders when ranked based on the expression of the target AXIN2. Moreover, high AXIN2 did not always correspond to elevated expression of other Wnt targets, which were activated in different proportions in individual cells. The uncoupling of Wnt target gene expression was also identified in single cell transcriptomics profiling of other Wnt-responding cell types, including HEK293T, murine developing forelimbs, and human colorectal cancer. Our finding underlines the necessity to identify additional mechanisms that explain the heterogeneity of the Wnt/beta-catenin-mediated transcriptional outputs in single cells.

  • 3.
    Örkenby, Lovisa
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Skog, Signe
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ekman, Helen
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Gozzo, Alessandro
    Linköping University, Department of Biomedical and Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
    Örtegren Kugelberg, Unn
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ramesh, Rashmi
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Magadi, Srivathsa
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Zambanini, Gianluca
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nätt, Daniel
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Öst, Anita
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Stress-sensitive dynamics of miRNAs and Elba1 in Drosophila embryogenesis2023In: Molecular Systems Biology, ISSN 1744-4292, E-ISSN 1744-4292, Vol. 19, no 5, article id e11148Article in journal (Refereed)
    Abstract [en]

    Early-life stress can result in life-long effects that impact adult health and disease risk, but little is known about how such programming is established and maintained. Here, we show that such epigenetic memories can be initiated in the Drosophila embryo before the major wave of zygotic transcription, and higher-order chromatin structures are established. An early short heat shock results in elevated levels of maternal miRNA and reduced levels of a subgroup of zygotic genes in stage 5 embryos. Using a Dicer-1 mutant, we show that the stress-induced decrease in one of these genes, the insulator-binding factor Elba1, is dependent on functional miRNA biogenesis. Reduction in Elba1 correlates with the upregulation of early developmental genes and promotes a sustained weakening of heterochromatin in the adult fly as indicated by an increased expression of the PEV w(m4h) reporter. We propose that maternal miRNAs, retained in response to an early embryonic heat shock, shape the subsequent de novo heterochromatin establishment that occurs during early development via direct or indirect regulation of some of the earliest expressed genes, including Elba1.

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  • 4.
    Nordin, Anna
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Zambanini, Gianluca
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Pagella, Pierfrancesco
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    The CUT & RUN suspect list of problematic regions of the genome2023In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 24, no 1, article id 185Article in journal (Refereed)
    Abstract [en]

    BackgroundCleavage Under Targets and Release Using Nuclease (CUT & RUN) is an increasingly popular technique to map genome-wide binding profiles of histone modifications, transcription factors, and co-factors. The ENCODE project and others have compiled blacklists for ChIP-seq which have been widely adopted: these lists contain regions of high and unstructured signal, regardless of cell type or protein target, indicating that these are false positives. While CUT & RUN obtains similar results to ChIP-seq, its biochemistry and subsequent data analyses are different. We found that this results in a CUT & RUN-specific set of undesired high-signal regions.ResultsWe compile suspect lists based on CUT & RUN data for the human and mouse genomes, identifying regions consistently called as peaks in negative controls. Using published CUT & RUN data from our and other labs, we show that the CUT & RUN suspect regions can persist even when peak calling is performed with SEACR or MACS2 against a negative control and after ENCODE blacklist removal. Moreover, we experimentally validate the CUT & RUN suspect lists by performing reiterative negative control experiments in which no specific protein is targeted, showing that they capture more than 80% of the peaks identified.ConclusionsWe propose that removing these problematic regions can substantially improve peak calling in CUT & RUN experiments, resulting in more reliable datasets.

  • 5.
    Pagella, Pierfrancesco
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Zambanini, Gianluca
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Ghezzi, Valeria
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Jauregi Miguel, Amaia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    The time-resolved genomic impact of Wnt/(3-catenin signaling2023In: CELL SYSTEMS, ISSN 2405-4712, Vol. 14, no 7, p. 563-581.e7Article in journal (Refereed)
    Abstract [en]

    Wnt signaling orchestrates gene expression via its effector, (3-catenin. However, it is unknown whether (3-cat-enin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT & RUN against (3-catenin, ATAC-seq, and perturba-tion assays in different cell types, we show that Wnt/(3-catenin physical targets are tissue-specific, (3-catenin "moves"on different loci over time, and its association to DNA accompanies changing chromatin accessi-bility landscapes that determine cell behavior. In particular, Wnt/(3-catenin progressively shapes the chro-matin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as "plastic."In HEK293T cells, on the other hand, Wnt/(3-catenin drives a transient chromatin open-ing, followed by re-establishment of the pre-stimulation state, a response that we define as "elastic."Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints. A record of this papers transparent peer review process is included in the supplemental information.

  • 6.
    Zambanini, Gianluca
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nordin, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Jonasson, Mattias
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Pagella, Pierfrancesco
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    A new CUT&RUN low volume-urea (LoV-U) protocol optimized for transcriptional co-factors uncovers Wnt/beta-catenin tissue-specific genomic targets2022In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 149, no 23, article id dev201124Article in journal (Refereed)
    Abstract [en]

    Upon WNT/beta-catenin pathway activation, stabilized beta-catenin travels to the nucleus where it associates with the TCF/LEF transcription factors, constitutively bound to genomic Wnt-responsive elements (WREs), to activate target gene transcription. Discovering the binding profile of beta-catenin is therefore required to unambiguously assign direct targets of WNT signaling. Cleavage under targets and release using nuclease (CUT&RUN) has emerged as prime technique for mapping the binding profile of DNA-interacting proteins. Here, we present a modified version of CUT&RUN, named LoV-U (low volume and urea), that enables the robust and reproducible generation of beta-catenin binding profiles, uncovering direct WNT/beta-catenin target genes in human cells, as well as in cells isolated from developing mouse tissues. CUT&RUN-LoV-U outperforms original CUT&RUN when targeting co-factors that do not bind the DNA, can profile all classes of chromatin regulators and is well suited for simultaneous processing of several samples. We believe that the application of our protocol will allow the detection of the complex system of tissue-specific WNT/beta-catenin target genes, together with other non-DNA-binding transcriptional regulators that act downstream of ontogenetically fundamental signaling cascades.

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  • 7.
    Barchiesi, Riccardo
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Chanthongdee, Kanat
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Mahidol Univ, Thailand.
    Petrella, Michele
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Xu, Li
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Esi
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Augier, Gaëlle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Coppola, Andrea
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Wiskerke, Joost
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Szczot, Ilona
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Domi, Ana
    Univ Gothenburg, Sweden.
    Adermark, Louise
    Univ Gothenburg, Sweden.
    Augier, Eric
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Psykiatricentrum, Psykiatriska kliniken i Linköping.
    Barbier, Estelle
    Linköping University, Department of Biomedical and Clinical Sciences, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences.
    An epigenetic mechanism for over-consolidation of fear memories2022In: Molecular Psychiatry, ISSN 1359-4184, E-ISSN 1476-5578, Vol. 27, no 12, p. 4893-4904Article in journal (Refereed)
    Abstract [en]

    Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2 knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2 KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2 KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2 KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

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  • 8.
    Pizzolato, Giulia
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Moparthi, Lavanya
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Koch, Stefan
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    The oncogenic transcription factor FOXQ1 is a differential regulator of Wnt target genes2022In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 135, no 19, article id jcs260082Article in journal (Refereed)
    Abstract [en]

    The forkhead box transcription factor FOXQ1 contributes to the pathogenesis of carcinomas. In colorectal cancers, FOXQ1 promotes tumour metastasis by inducing epithelial-to-mesenchymal transition (EMT) of cancer cells. FOXQ1 may exacerbate cancer by activating the oncogenic Wnt/beta-catenin signalling pathway. However, the role of FOXQ1 in the Wnt pathway remains to be resolved. Here, we report that FOXQ1 is an activator of Wnt-induced transcription and regulator of beta-catenin target gene expression. Upon Wnt pathway activation, FOXQ1 synergises with the beta-catenin nuclear complex to boost the expression of major Wnt targets. In parallel, we find that FOXQ1 controls the differential expression of various Wnt target genes in a beta-catenin-independent manner. Using RNA sequencing of colorectal cancer cell lines, we show that Wnt signalling and FOXQ1 converge on a transcriptional programme linked to EMT and cell migration. Additionally, we demonstrate that FOXQ1 occupies Wnt-responsive elements in beta-catenin target gene promoters and recruits a similar set of co-factors to the beta-catenin-associated transcription factor Tcf711. Taken together, our results indicate a multifaceted role of FOXQ1 in Wnt/beta-catenin signalling, which may drive the metastasis of colorectal cancers.

  • 9.
    Diener, Johanna
    et al.
    Univ Zurich, Switzerland.
    Baggiolini, Arianna
    Univ Zurich, Switzerland; Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Pernebrink, Mattias
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Dalcher, Damian
    Univ Zurich, Switzerland.
    Lerra, Luigi
    Univ Zurich, Switzerland.
    Cheng, Phil F.
    Univ Hosp Zurich, Switzerland.
    Varum, Sandra
    Univ Zurich, Switzerland.
    Hausel, Jessica
    Univ Zurich, Switzerland.
    Stierli, Salome
    Univ Zurich, Switzerland.
    Treier, Mathias
    Max Delbruck Ctr Mol Med, Germany; Charite Univ Med Berlin, Germany.
    Studer, Lorenz
    Mem Sloan Kettering Canc Ctr, NY 10021 USA.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Levesque, Mitchell P.
    Univ Hosp Zurich, Switzerland.
    Dummer, Reinhard
    Univ Hosp Zurich, Switzerland.
    Santoro, Raffaella
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Sommer, Lukas
    Univ Zurich, Switzerland.
    Epigenetic control of melanoma cell invasiveness by the stem cell factor SALL42021In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 5056Article in journal (Refereed)
    Abstract [en]

    Melanoma cells rely on developmental programs during tumor initiation and progression. Here we show that the embryonic stem cell (ESC) factor Sall4 is re-expressed in the Tyr::Nras(Q61K); Cdkn2a(-/-) melanoma model and that its expression is necessary for primary melanoma formation. Surprisingly, while Sall4 loss prevents tumor formation, it promotes micrometastases to distant organs in this melanoma-prone mouse model. Transcriptional profiling and in vitro assays using human melanoma cells demonstrate that SALL4 loss induces a phenotype switch and the acquisition of an invasive phenotype. We show that SALL4 negatively regulates invasiveness through interaction with the histone deacetylase (HDAC) 2 and direct co-binding to a set of invasiveness genes. Consequently, SALL4 knock down, as well as HDAC inhibition, promote the expression of an invasive signature, while inhibition of histone acetylation partially reverts the invasiveness program induced by SALL4 loss. Thus, SALL4 appears to regulate phenotype switching in melanoma through an HDAC2-mediated mechanism. Melanoma cells can switch between proliferative and invasive phenotypes. Here the authors show that the embryonic stem cell factor Sall4 is a negative regulator of melanoma phenotype switching where its loss leads to the acquisition of an invasive phenotype, due to derepression of invasiveness genes.

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  • 10.
    Pagin, Miriam
    et al.
    Univ Milano Bicocca, Italy.
    Pernebrink, Mattias
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Pitasi, Mattia
    Univ Milano Bicocca, Italy.
    Malighetti, Federica
    Univ Milano Bicocca, Italy.
    Ngan, Chew-Yee
    Jackson Lab Genom Med, CT 06032 USA.
    Ottolenghi, Sergio
    Univ Milano Bicocca, Italy.
    Pavesi, Giulio
    Univ Milan, Italy.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nicolis, Silvia K.
    Univ Milano Bicocca, Italy.
    FOS Rescues Neuronal Differentiation of Sox2-Deleted Neural Stem Cells by Genome-Wide Regulation of Common SOX2 and AP1(FOS-JUN) Target Genes2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 7, article id 1757Article in journal (Refereed)
    Abstract [en]

    The transcription factor SOX2 is important for brain development and for neural stem cells (NSC) maintenance. Sox2-deleted (Sox2-del) NSC from neonatal mouse brain are lost after few passages in culture. Two highly expressed genes, Fos and Socs3, are strongly downregulated in Sox2-del NSC; we previously showed that Fos or Socs3 overexpression by lentiviral transduction fully rescues NSCs long-term maintenance in culture. Sox2-del NSC are severely defective in neuronal production when induced to differentiate. NSC rescued by Sox2 reintroduction correctly differentiate into neurons. Similarly, Fos transduction rescues normal or even increased numbers of immature neurons expressing beta-tubulinIII, but not more differentiated markers (MAP2). Additionally, many cells with both beta-tubulinIII and GFAP expression appear, indicating that FOS stimulates the initial differentiation of a "mixed" neuronal/glial progenitor. The unexpected rescue by FOS suggested that FOS, a SOX2 transcriptional target, might act on neuronal genes, together with SOX2. CUT&RUN analysis to detect genome-wide binding of SOX2, FOS, and JUN (the AP1 complex) revealed that a high proportion of genes expressed in NSC are bound by both SOX2 and AP1. Downregulated genes in Sox2-del NSC are highly enriched in genes that are also expressed in neurons, and a high proportion of the "neuronal" genes are bound by both SOX2 and AP1.

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  • 11.
    Buechel, David
    et al.
    Univ Basel, Switzerland.
    Sugiyama, Nami
    Univ Basel, Switzerland.
    Rubinstein, Natalia
    Univ Buenos Aires, Argentina.
    Saxena, Meera
    Univ Basel, Switzerland.
    Kalathur, Ravi K. R.
    Univ Basel, Switzerland; Royal Childrens Hosp, Australia.
    Luond, Fabiana
    Univ Basel, Switzerland.
    Vafaizadeh, Vida
    Univ Basel, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Christofori, Gerhard
    Univ Basel, Switzerland.
    Parsing beta-catenins cell adhesion and Wnt signaling functions in malignant mammary tumor progression2021In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 118, no 34, article id e2020227118Article in journal (Refereed)
    Abstract [en]

    During malignant progression, epithelial cancer cells dissolve their cell-cell adhesion and gain invasive features. By virtue of its dual function, beta-catenin contributes to cadherin-mediated cell-cell adhesion, and it determines the transcriptional output of Wnt signaling: via its N terminus, it recruits the signaling coactivators Bd9 and Pygo-pus, and via the C terminus, it interacts with the general transcriptional machinery. This duality confounds the simple loss-of-function analysis of Wnt signaling in cancer progression. In many cancer types including breast cancer, the functional contribution of beta-catenins transcriptional activities, as compared to its adhesion functions, to tumor progression has remained elusive. Employing the mouse mammary tumor virus (MMTV)-PyMT mouse model of metastatic breast cancer, we compared the complete elimination of beta-catenin with the specific ablation of its signaling outputs in mammary tumor cells. Notably, the complete lack of beta-catenin resulted in massive apoptosis of mammary tumor cells. In contrast, the loss of beta-catenins transcriptional activity resulted in a reduction of primary tumor growth, tumor invasion, and metastasis formation in vivo. These phenotypic changes were reflected by stalled cell cycle progression and diminished epithelial-mesenchymal transition (EMT) and cell migration of breast cancer cells in vitro. Transcriptome analysis revealed subsets of genes which were specifically regulated by beta-catenins transcriptional activities upon stimulation with Wnt3a or during TGF-beta-induced EMT. Our results uncouple the signaling from the adhesion function of beta-catenin and underline the importance of Wnt/beta-catenin-dependent transcription in malignant tumor progression of breast cancer.

  • 12.
    Pagin, Miriam
    et al.
    Univ Milano Bicocca, Italy.
    Pernebrink, Mattias
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Giubbolini, Simone
    Univ Milano Bicocca, Italy.
    Barone, Cristiana
    Univ Milano Bicocca, Italy.
    Sambruni, Gaia
    Univ Milano Bicocca, Italy.
    Zhu, Yanfen
    Jackson Lab Genom Med, CT USA.
    Chiara, Matteo
    Univ Milan, Italy.
    Ottolenghi, Sergio
    Univ Milano Bicocca, Italy.
    Pavesi, Giulio
    Univ Milan, Italy.
    Wei, Chia-Lin
    Jackson Lab Genom Med, CT USA.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Nicolis, Silvia K.
    Univ Milano Bicocca, Italy.
    Sox2 controls neural stem cell self-renewal through a Fos-centered gene regulatory network2021In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 39, no 8, p. 1107-1119Article in journal (Refereed)
    Abstract [en]

    The Sox2 transcription factor is necessary for the long-term self-renewal of neural stem cells (NSCs). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, into Sox2-deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2), individually or in combination. Fos alone rescued long-term proliferation, as shown by in vitro cell growth and clonal analysis. Furthermore, pharmacological inhibition by T-5224 of FOS/JUN AP1 complex binding to its targets decreased cell proliferation and expression of the putative target Suppressor of cytokine signaling 3 (Socs3). Additionally, Fos requirement for efficient long-term proliferation was demonstrated by the reduction of NSC clones capable of long-term expansion following CRISPR/Cas9-mediated Fos inactivation. Previous work showed that the Socs3 gene is strongly downregulated following Sox2 deletion, and its re-expression by lentiviral transduction rescues long-term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 re-expression in Sox2-deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA-PET data, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; furthermore, we provide direct evidence for FOS and JUN binding on Socs3 promoter, suggesting direct transcriptional regulation. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long-term maintenance.

  • 13.
    Doumpas, Nikolaos
    et al.
    Univ Zurich, Switzerland.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Narula, Smarth
    McMaster Univ, Canada.
    Moreira, Steven
    McMaster Univ, Canada.
    Doble, Bradley W.
    McMaster Univ, Canada; Univ Manitoba, Canada; Univ Manitoba, Canada.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Basler, Konrad
    Univ Zurich, Switzerland.
    TCF/LEF regulation of the topologically associated domain ADI promotes mESCs to exit the pluripotent ground state2021In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 36, no 11, article id 109705Article in journal (Refereed)
    Abstract [en]

    Mouse embryonic stem cells (mESCs) can bemaintained in vitro in defined N2B27 medium supplemented with two chemical inhibitors for GSK3 and MEK (2i) and the cytokine leukemia inhibitory factor (LIF), which act synergistically to promote self-renewal and pluripotency. Here, we find that genetic deletion of the four genes encoding the TCF/LEF transcription factors confersm ESCs with the ability to self-renew in N2B27 medium alone. TCF/LEF quadruple knockout (qKO) mESCs display dysregulation of several genes, including Aire, Dnmt3l, and IcosL, located adjacent to each other within a topologically associated domain (TAD). Aire, Dnmt3l, and IcosL appear to be regulated by TCF/LEF in a beta-catenin independent manner. Moreover, downregulation of Aire and Dnmt3l in wild-type mESCs mimics the loss of TCF/LEF and increases mESC survival in the absence of 2iL. Hence, this study identifies TCF/LEF effectors that mediate exit from the pluripotent state.

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  • 14.
    Fugazza, Cristina
    et al.
    Università di Milano-Bicocca, Italy.
    Barbarani, Gloria
    Università di Milano-Bicocca, Italy.
    Elangovan, Sudharshan
    Università di Milano-Bicocca, Italy.
    Marini, Maria Giuseppina
    Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle Ricerche, Italy.
    Giolitto, Serena
    Università di Milano-Bicocca, Italy.
    Font-Monclus, Isaura
    Università di Milano-Bicocca, Italy.
    Marongiu, Maria Franca
    Istituto di Ricerca Genetica e Biomedica del Consiglio Nazionale delle Ricerche, Italy.
    Manunza, Laura
    Universita degli Studi di Cagliari, Italy.
    Strouboulis, John
    King's College London, United Kingdom.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Gasparri, Fabio
    Nerviano Medical Sciences S.r.l., Nerviano, Italy.
    Barabino, Silvia M. L.
    Università di Milano-Bicocca, Milano, Italy.
    Nakamura, Yukio
    RIKEN BioResource Research Center, Japan.
    Ottolenghi, Sergio
    Università di Milano-Bicocca, Milano, Italy.
    Moi, Paolo
    Universita degli Studi di Cagliari, Italy.
    Ronchi, Antonella Ellena
    Università di Milano-Bicocca, Milano, Italy.
    The Coup-TFII orphan nuclear receptor is an activator of the γ-globin gene2021In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 106, no 2, p. 474-482Article in journal (Refereed)
    Abstract [en]

    The human fetal γ-globin gene is repressed in the adult stage through complex regulatory mechanisms involving transcription factors and epigenetic modifiers. Reversing γ-globin repression, or maintaining its expression by manipulating regulatory mechanisms, has become a major clinical goal in the treatment of β-hemoglobinopathies. Here, we identify the orphan nuclear receptor Coup-TFII (NR2F2/ARP-1) as an embryonic/fetal stage activator of γ-globin expression. We show that Coup-TFII is expressed in early erythropoiesis of yolk sac origin, together with embryonic/fetal globins. When overexpressed in adult cells (including peripheral blood cells from human healthy donors and β039 thalassemic patients) Coup-TFII activates the embryonic/fetal globins genes, overcoming the repression imposed by the adult erythroid environment. Conversely, the knock-out of Coup-TFII increases the β/γ+β globin ratio. Molecular analysis indicates that Coup-TFII binds in vivo to the β-locus and contributes to its conformation. Overall, our data identify Coup-TFII as a specific activator of the γ-globin gene.

  • 15.
    Vafaizadeh, Vida
    et al.
    Univ Basel, Switzerland.
    Buechel, David
    Univ Basel, Switzerland.
    Rubinstein, Natalia
    Univ Buenos Aires, Argentina.
    Kalathur, Ravi K. R.
    Univ Basel, Switzerland; Royal Childrens Hosp, Australia.
    Bazzani, Lorenzo
    Univ Basel, Switzerland; Univ Siena, Italy.
    Saxena, Meera
    Univ Basel, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Christofori, Gerhard
    Univ Basel, Switzerland.
    The interactions of Bcl9/Bcl9L with beta-catenin and Pygopus promote breast cancer growth, invasion, and metastasis2021In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 40, no 43, p. 6195-6209Article in journal (Refereed)
    Abstract [en]

    Canonical Wnt/beta-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of beta-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9 and Bcl9L resulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with beta-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of beta-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the beta-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGF beta treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the "just-right" hypothesis of Wnt-driven tumor progression.

  • 16.
    Söderholm, Simon
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    The WNT/beta-catenin dependent transcription: A tissue-specific business2021In: Wiley Interdisciplinary Reviews: Systems Biology and Medicine, ISSN 1939-5094, E-ISSN 1939-005X, Vol. 13, no 3, article id e1511Article, review/survey (Refereed)
    Abstract [en]

    beta-catenin-mediated Wnt signaling is an ancient cell-communication pathway in which beta-catenin drives the expression of certain genes as a consequence of the trigger given by extracellular WNT molecules. The events occurring from signal to transcription are evolutionarily conserved, and their final output orchestrates countless processes during embryonic development and tissue homeostasis. Importantly, a dysfunctional Wnt/beta-catenin pathway causes developmental malformations, and its aberrant activation is the root of several types of cancer. A rich literature describes the multitude of nuclear players that cooperate with beta-catenin to generate a transcriptional program. However, a unified theory of how beta-catenin drives target gene expression is still missing. We will discuss two types of beta-catenin interactors: transcription factors that allow beta-catenin to localize at target regions on the DNA, and transcriptional co-factors that ultimately activate gene expression. In contrast to the presumed universality of beta-catenin s action, the ensemble of available evidence suggests a view in which beta-catenin drives a complex system of responses in different cells and tissues. A malleable armamentarium of players might interact with beta-catenin in order to activate the right "canonical" targets in each tissue, developmental stage, or disease context. Discovering the mechanism by which each tissue-specific beta-catenin response is executed will be crucial to comprehend how a seemingly universal pathway fosters a wide spectrum of processes during development and homeostasis. Perhaps more importantly, this could ultimately inform us about which are the tumor-specific components that need to be targeted to dampen the activity of oncogenic beta-catenin. This article is categorized under: Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics Cancer > Stem Cells and Development

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  • 17.
    Saxena, Meera
    et al.
    Univ Basel, Switzerland.
    Kalathur, Ravi K. R.
    Univ Basel, Switzerland; Royal Childrens Hosp, Australia.
    Rubinstein, Natalia
    Univ Basel, Switzerland; Univ Buenos Aires, Argentina.
    Vettiger, Andrea
    Univ Basel, Switzerland; Harvard Med Sch, MA 02115 USA.
    Sugiyama, Nami
    Univ Basel, Switzerland.
    Neutzner, Melanie
    Univ Basel, Switzerland.
    Coto-Llerena, Mairene
    Univ Hosp Basel, Switzerland.
    Kancherla, Venkatesh
    Univ Hosp Basel, Switzerland.
    Ercan, Caner
    Univ Hosp Basel, Switzerland.
    Piscuoglio, Salvatore
    Univ Hosp Basel, Switzerland.
    Fischer, Jonas
    Univ Basel, Switzerland.
    Fagiani, Ernesta
    Univ Basel, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Christofori, Gerhard
    Univ Basel, Switzerland.
    A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 17, p. 3631-3648Article in journal (Refereed)
    Abstract [en]

    Pygopus 2 (Pygo2) is a coactivator of Wnt/b-catenin signaling that can bind bi- or trimethylated lysine 4 of histone-3 (H3K4me(2/3)) and participate in chromatin reading and writing. It remains unknown whether the Pygo2-H3K4me(2/3) association has a functional relevance in breast cancer progression in vivo. To investigate the functional relevance of histone-binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model where binding of Pygo2 to H3K4me(2/3) was rendered ineffective. Loss of Pygo2-histone interaction resulted in smaller, differentiated, and less metastatic tumors, due, in part, to decreased canonical Wnt/b-catenin signaling. RNA- and ATAC-sequencing analyses of tumor-derived cell lines revealed downregulation of TGF beta signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate that could be reversed by inhibition of PDGFR activity. Mechanistically, the Pygo2-histone interaction potentiated Wnt/beta-catenin signaling, in part, by repressing the expression of Wnt signaling antagonists. Furthermore, Pygo2 and beta-catenin regulated the expression of miR-29 family members, which, in turn, repressed PDGFR expression to promote dedifferentiation of wild-type Pygo2 mammary epithelial tumor cells. Collectively, these results demonstrate that the histone binding function of Pygo2 is important for driving dedifferentiation and malignancy of breast tumors, and loss of this binding activates various differentiation pathways that attenuate primary tumor growth and metastasis formation. Interfering with the Pygo2-H3K4me(2/3) interaction may therefore serve as an attractive therapeutic target for metastatic breast cancer. Significance: Pygo2 represents a potential therapeutic target in metastatic breast cancer, as its histone-binding capability promotes beta-catenin-mediated Wnt signaling and transcriptional control in breast cancer cell dedifferentiation, EMT, and metastasis.

  • 18.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland; Netherlands Canc Inst, Netherlands.
    Borrelli, Costanza
    Swiss Fed Inst Technol, Switzerland.
    Jauregi Miguel, Amaia
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderholm, Simon
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    Brutsch, Salome
    Univ Zurich, Switzerland.
    Doumpas, Nikolaos
    Univ Zurich, Switzerland.
    Reichmuth, Jan
    Univ Zurich, Switzerland.
    Murphy-Seiler, Fabienne
    Ecole Polytech Fed Lausanne EPFL, Switzerland.
    Aguet, Michel
    Ecole Polytech Fed Lausanne EPFL, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Moor, Andreas E.
    Swiss Fed Inst Technol, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology. Linköping University, Faculty of Medicine and Health Sciences.
    TBX3 acts as tissue-specific component of the Wnt/beta-catenin transcriptional complex2020In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e58123Article in journal (Refereed)
    Abstract [en]

    BCL9 and PYGO are beta-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of beta-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the beta-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a beta-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/beta-catenin-dependent transcriptional complex.

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  • 19.
    Kabakci, Zeynep
    et al.
    Univ Zurich, Switzerland.
    Kappeli, Simon
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Konig, Christiane
    Univ Zurich, Switzerland.
    Toggweiler, Janine
    Univ Zurich, Switzerland.
    Gentili, Christian
    Univ Zurich, Switzerland.
    Ribaudo, Giovanni
    Univ Padua, Italy.
    Zagotto, Giuseppe
    Univ Padua, Italy.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Pinna, Lorenzo A.
    Univ Padua, Italy.
    Cozza, Giorgio
    Univ Padua, Italy.
    Ferrari, Stefano
    Univ Zurich, Switzerland.
    Pharmacophore-guided discovery of CDC25 inhibitors causing cell cycle arrest and tumor regression2019In: Scientific Reports, E-ISSN 2045-2322, Vol. 9, article id 1335Article in journal (Refereed)
    Abstract [en]

    CDC25 phosphatases play a key role in cell cycle transitions and are important targets for cancer therapy. Here, we set out to discover novel CDC25 inhibitors. Using a combination of computational methods, we defined a minimal common pharmacophore in established CDC25 inhibitors and performed virtual screening of a proprietary library. Based on the availability of crystal structures for CDC25A and CDC25B, we implemented a molecular docking strategy and carried out hit expansion/optimization. Enzymatic assays revealed that naphthoquinone scaffolds were the most promising CDC25 inhibitors among selected hits. At the molecular level, the compounds acted through a mixed-type mechanism of inhibition of phosphatase activity, involving reversible oxidation of cysteine residues. In 2D cell cultures, the compounds caused arrest of the cell cycle at the G1/S or at the G2/M transition. Mitotic markers analysis and time-lapse microscopy confirmed that CDK1 activity was impaired and that mitotic arrest was followed by death. Finally, the compounds induced differentiation, accompanied by decreased stemness properties, in intestinal crypt stem cell-derived Apc/K-Ras-mutant mouse organoids, and led to tumor regression and reduction of metastatic potential in zebrafish embryo xenografts used as in vivo model.

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  • 20.
    Salazar, Valerie S.
    et al.
    Harvard Sch Dent Med, MA 02115 USA; Univ Zurich, Switzerland.
    Capelo, Luciane P.
    Harvard Sch Dent Med, MA 02115 USA; Univ Fed Sao Paulo, Brazil.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Zimmerli, Dario
    Univ Zurich, Switzerland.
    Gosalia, Nehal
    Regeneron Pharmaceut, NY USA.
    Pregizer, Steven
    Harvard Sch Dent Med, MA 02115 USA.
    Cox, Karen
    Harvard Sch Dent Med, MA 02115 USA.
    Ohte, Satoshi
    Harvard Sch Dent Med, MA 02115 USA; Kitasato Univ, Japan.
    Feigenson, Marina
    Harvard Sch Dent Med, MA 02115 USA.
    Gamer, Laura
    Harvard Sch Dent Med, MA 02115 USA.
    Nyman, Jeffry S.
    Vanderbilt Univ, TN USA.
    Carey, David J.
    Geisinger Hlth Syst, PA USA.
    Economides, Aris
    Regeneron Pharmaceut, NY USA.
    Basler, Konrad
    Harvard School of Dental Medicine, Boston, United States.
    Rosen, Vicki
    Harvard Sch Dent Med, MA 02115 USA.
    Reactivation of a developmental Bmp2 signaling center is required for therapeutic control of the murine periosteal niche2019In: eLIFE, E-ISSN 2050-084X, Vol. 8, article id e42386Article in journal (Refereed)
    Abstract [en]

    Two decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only Bmp2 in the Prx1-Cre lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of Sp7 via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of BMP2 and GRHL3 are associated with increased risk of fractures.

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  • 21.
    Doumpas, Nikolaos
    et al.
    Univ Zurich, Switzerland.
    Lampart, Franziska
    Univ Zurich, Switzerland.
    Robinson, Mark D.
    Univ Zurich, Switzerland.
    Lentini, Antonio
    Univ Zurich, Switzerland.
    Nestor, Colm
    Linköping University, Department of Clinical and Experimental Medicine, Division of Children's and Women's health. Linköping University, Faculty of Medicine and Health Sciences.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    TCF/LEF dependent and independent transcriptional regulation of Wnt/beta-catenin target genes2019In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 38, no 2, article id e98873Article in journal (Refereed)
    Abstract [en]

    During canonical Wnt signalling, the activity of nuclear beta-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of beta-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that beta-catenin occupied specific genomic regions in the absence of TCF/LEF. Finally, we revealed the existence of a transcriptional activity of beta-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as beta-catenin-GHOST response. Collectively, this study uncovers a previously neglected modus operandi of beta-catenin that bypasses the TCF/LEF transcription factors.

  • 22.
    Varum, Sandra
    et al.
    University of Zurich, Switzerland.
    Baggiolini, Arianna
    University of Zurich, Switzerland.
    Zurkirchen, Luis
    University of Zurich, Switzerland.
    Atak, Zeynep Kalender
    Laboratory of Computational Biology, Belgium; Department of Human Genetics, Belgium.
    Cantù, Claudio
    University of Zurich, Switzerland.
    Marzorati, Elisa
    University of Zurich, Switzerland.
    Bossart, Raphaël
    University of Zurich, Switzerland.
    Wouters, Jasper
    Laboratory of Computational Biology, Leuven, Belgium; KU Leuven, Leuven, Belgium.
    Häusel, Jessica
    University of Zurich, Switzerland.
    Tuncer, Eylül
    University of Zurich, Switzerland.
    Zingg, Daniel
    University of Zurich, Switzerland.
    Veen, Dominiek
    University of Zurich, Switzerland.
    John, Nessy
    University of Zurich, Switzerland.
    Balz, Marcel
    University of Zurich, Switzerland.
    Levesque, Mitchell P
    University of Zurich, Switzerland.
    Basler, Konrad
    University of Zurich, Switzerland.
    Aerts, Stein
    University of Zurich, Switzerland.
    Zamboni, Nicola
    University of Zurich, Switzerland.
    Dummer, Reinhard
    University of Zurich, Switzerland.
    Sommer, Lukas
    University of Zurich, Switzerland.
    Yin Yang 1 Orchestrates a Metabolic Program Required for Both Neural Crest Development and Melanoma Formation2019In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 24, no 4, p. 637-653.e9Article in journal (Refereed)
    Abstract [en]

    Increasing evidence suggests that cancer cells highjack developmental programs for disease initiation and progression. Melanoma arises from melanocytes that originate during development from neural crest stem cells (NCSCs). Here, we identified the transcription factor Yin Yang 1 (Yy1) as an NCSCs regulator. Conditional deletion of Yy1 in NCSCs resulted in stage-dependent hypoplasia of all major neural crest derivatives due to decreased proliferation and increased cell death. Moreover, conditional ablation of one Yy1 allele in a melanoma mouse model prevented tumorigenesis, indicating a particular susceptibility of melanoma cells to reduced Yy1 levels. Combined RNA sequencing (RNA-seq), chromatin immunoprecipitation (ChIP)-seq, and untargeted metabolomics demonstrated that YY1 governs multiple metabolic pathways and protein synthesis in both NCSCs and melanoma. In addition to directly regulating a metabolic gene set, YY1 can act upstream of MITF/c-MYC as part of a gene regulatory network controlling metabolism. Thus, both NCSC development and melanoma formation depend on an intricate YY1-controlled metabolic program.

  • 23.
    Zurkirchen, Luis
    et al.
    Univ Zurich, Switzerland.
    Varum, Sandra
    Univ Zurich, Switzerland.
    Giger, Sonja
    Univ Zurich, Switzerland.
    Klug, Annika
    Univ Zurich, Switzerland.
    Hausel, Jessica
    Univ Zurich, Switzerland.
    Bossart, Raphael
    Univ Zurich, Switzerland.
    Zemke, Martina
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Atak, Zeynep Kalender
    Katholieke Univ Leuven, Belgium.
    Zamboni, Nicola
    Swiss Fed Inst Technol, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Sommer, Lukas
    Univ Zurich, Switzerland.
    Yin Yang 1 sustains biosynthetic demands during brain development in a stage-specific manner2019In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 2192Article in journal (Refereed)
    Abstract [en]

    The transcription factor Yin Yang 1 (YY1) plays an important role in human disease. It is often overexpressed in cancers and mutations can lead to a congenital haploinsufficiency syndrome characterized by craniofacial dysmorphisms and neurological dysfunctions, consistent with a role in brain development. Here, we show that Yy1 controls murine cerebral cortex development in a stage-dependent manner. By regulating a wide range of metabolic pathways and protein translation, Yy1 maintains proliferation and survival of neural progenitor cells (NPCs) at early stages of brain development. Despite its constitutive expression, however, the dependence on Yy1 declines over the course of corticogenesis. This is associated with decreasing importance of processes controlled by Yy1 during development, as reflected by diminished protein synthesis rates at later developmental stages. Thus, our study unravels a novel role for Yy1 as a stage-dependent regulator of brain development and shows that biosynthetic demands of NPCs dynamically change throughout development.

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  • 24.
    Mitsiadis, Thimios A.
    et al.
    Orofacial Development and Regeneration, Centre for Dental Medicine, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Jimenez-Rojo, Lucia
    Orofacial Development and Regeneration, Centre for Dental Medicine, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Editorial: Signaling Pathways in Developing and Pathological Tissues and Organs of the Craniofacial Complex2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, p. 1-3, article id 1015Article in journal (Other academic)
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  • 25.
    Cantù, Claudio
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Felker, Anastasia
    Univ Zurich, Switzerland.
    Zimmerli, Dario
    Univ Zurich, Switzerland.
    Prummel, Karin D.
    Univ Zurich, Switzerland.
    Cabello, Elena M.
    Univ Zurich, Switzerland.
    Chiavacci, Elena
    Univ Zurich, Switzerland; Int Ctr Genet Engn and Biotechnol ICGEB Trieste, Italy.
    Mendez-Acevedo, Kevin M.
    Max Delbruck Ctr Mol Med, Germany.
    Kirchgeorg, Lucia
    Univ Zurich, Switzerland.
    Burger, Sibylle
    Univ Zurich, Switzerland.
    Ripoll, Jorge
    Univ Carlos III Madrid, Spain.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Vilain, Nathalie
    Ecole Polytech Fed Lausanne, Switzerland.
    Aguet, Michel
    Ecole Polytech Fed Lausanne, Switzerland.
    Burger, Alexa
    Univ Zurich, Switzerland.
    Panakova, Daniela
    Max Delbruck Ctr Mol Med, Germany; Deutsch Zentrum Herz Kreislauf Forsch DZHK, Germany.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Mosimann, Christian
    Univ Zurich, Switzerland.
    Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/beta-catenin signaling2018In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 32, no 21-22, p. 1443-1458Article in journal (Refereed)
    Abstract [en]

    Bcl9 and Pygopus (Pygo) are obligate Wnt/beta-catenin cofactors in Drosophila, yet their contribution to Wnt signaling during vertebrate development remains unresolved. Combining zebrafish and mouse genetics, we document a conserved, beta-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development. Disrupting the beta-catenin-BCL9-Pygo complex results in a broadly maintained canonical Wnt response yet perturbs heart development and proper expression of key cardiac regulators. Our work highlights BCL9 and Pygo as selective beta-catenin cofactors in a subset of canonical Wnt responses during vertebrate development. Moreover, our results implicate alterations in BCL9 and BCL9L in human congenital heart defects.

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  • 26.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland.
    Cecconi, Virginia
    Univ Zurich, Switzerland.
    Valenta, Tomas
    Univ Zurich, Switzerland.
    Hausmann, George
    Univ Zurich, Switzerland.
    Cantù, Claudio
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Univ Zurich, Switzerland.
    Restivo, Gaetana
    Univ Hosp Zurich, Switzerland.
    Hafner, Jurg
    Univ Hosp Zurich, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    van den Broek, Maries
    Univ Zurich, Switzerland.
    WNT ligands control initiation and progression of human papillomavirus-driven squamous cell carcinoma2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 27, p. 3753-3762Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/beta-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

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  • 27.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Pagella, Pierfrancesco
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    Shajiei, Tania D
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Mitsiadis, Thimios A
    Orofacial Development and Regeneration, Institute of Oral Biology, Center of Dental Medicine, University of Zurich, 8032 Zurich, Switzerland.
    A cytoplasmic role of Wnt/β-catenin transcriptional cofactors Bcl9, Bcl9l, and Pygopus in tooth enamel formation.2017In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 10, no 465, article id eaah4598Article in journal (Refereed)
    Abstract [en]

    Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.

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  • 28.
    Mitsiadis, Thimios A
    et al.
    Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, Medical Faculty, University of Zurich, Zurich, Switzerland.
    Pagella, Pierfrancesco
    Orofacial Development and Regeneration, Institute of Oral Biology, Centre for Dental Medicine, Medical Faculty, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
    Early Determination of the Periodontal Domain by the Wnt-Antagonist Frzb/Sfrp3.2017In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 8, article id 936Article in journal (Refereed)
    Abstract [en]

    Odontogenesis results from the continuous and reciprocal interaction between cells of the oral epithelium and cranial neural crest-derived mesenchyme. The canonical Wnt signaling pathway plays a fundamental role in mediating these interactions from the earliest stages of tooth development. Here we analyze by in situ hybridization the expression patterns of the extracellular Wnt antagonist Frzb/Sfrp3. Although Frzb is expressed in dental mesenchymal cells from the earliest stages of odontogenesis, its expression is absent from a tiny population of mesenchymal cells immediately adjacent to the invaginating dental epithelium. Cell proliferation studies using BrdU showed that the Frzb expressing and Frzb non-expressing cell populations display different proliferative behavior during the initial stages of odontogenesis. DiI-mediated cell-fate tracing studies demonstrated that the Frzb expressing cells contribute to the formation of the dental follicle, the future periodontium. In contrast, the Frzb non-expressing cells give rise to the dental pulp. The present results indicate that Frzb is discriminating the presumptive periodontal territory from the rest of the dental mesenchyme from the very beginning of odontogenesis, where it might act as a barrier for the diffusion of Wnt molecules, thus regulating the activation of Wnt-dependent transcription within dental tissues.

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  • 29.
    Pagella, Pierfrancesco
    et al.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Cantù, Claudio
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Mitsiadis, Thimios A.
    Orofacial Development & Regeneration, Institute of Oral Biology, University of Zurich, Zurich, Switzerland.
    Linking dental pathologies and cancer via Wnt signalling2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99213-99214Article in journal (Refereed)
  • 30.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Angonin, Diane
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Marcy, Guillaume
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pieropan, Francesca
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Rivera, Andrea
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Donega, Vanessa
    Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Cantù, Claudio
    IMLS, University of Zurich, Zurich, Switzerland.
    Williams, Gareth
    Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London, United Kingdom.
    Berninger, Benedikt
    Adult Neurogenesis and Cellular Reprogramming, Institute of Physiological Chemistry, University Medical Centre of the Johannes Gutenberg University Mainz, Germany / Focus Program Translational Neuroscience, Johannes Gutenberg University Mainz, Germany.
    Butt, Arthur M
    School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem Cell and Brain Research Institute U1208, Bron, France.
    Pharmacogenomic identification of small molecules for lineage specific manipulation of subventricular zone germinal activity2017In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 15, no 3, article id e2000698Article in journal (Refereed)
    Abstract [en]

    Strategies for promoting neural regeneration are hindered by the difficulty of manipulating desired neural fates in the brain without complex genetic methods. The subventricular zone (SVZ) is the largest germinal zone of the forebrain and is responsible for the lifelong generation of interneuron subtypes and oligodendrocytes. Here, we have performed a bioinformatics analysis of the transcriptome of dorsal and lateral SVZ in early postnatal mice, including neural stem cells (NSCs) and their immediate progenies, which generate distinct neural lineages. We identified multiple signaling pathways that trigger distinct downstream transcriptional networks to regulate the diversity of neural cells originating from the SVZ. Next, we used a novel in silico genomic analysis, searchable platform-independent expression database/connectivity map (SPIED/CMAP), to generate a catalogue of small molecules that can be used to manipulate SVZ microdomain-specific lineages. Finally, we demonstrate that compounds identified in this analysis promote the generation of specific cell lineages from NSCs in vivo, during postnatal life and adulthood, as well as in regenerative contexts. This study unravels new strategies for using small bioactive molecules to direct germinal activity in the SVZ, which has therapeutic potential in neurodegenerative diseases.

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  • 31.
    Zimmerli, Dario
    et al.
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zürich, Zürich, Switzerland.
    Pharmacological interventions in the Wnt pathway: inhibition of Wnt secretion versus disrupting the protein-protein interfaces of nuclear factors2017In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 174, no 24, p. 4600-4610Article in journal (Refereed)
    Abstract [en]

    Mutations in components of the Wnt pathways are a frequent cause of many human diseases, particularly cancer. Despite the fact that a causative link between aberrant Wnt signalling and many types of human cancers was established more than a decade ago, no Wnt signalling inhibitors have made it into the clinic so far. One reason for this is that no pathway-specific kinase is known. Additionally, targeting the protein-protein interactions needed to transduce the signal has not met with success so far. Complicating the search for and use of inhibitors is the complexity of the cascades triggered by the Wnts and their paramount biological importance. Wnt/β-catenin signalling is involved in virtually all aspects of embryonic development and in the control of the homeostasis of adult tissues. Encouragingly, however, in recent years, first successes with Wnt-pathway inhibitors have been reported in mouse models of disease. In this review, we summarize possible roads to follow during the quest to pharmacologically modulate the Wnt signalling pathway in cancer.

  • 32.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Zürich, Switzerland.
    Unexpected survival of mice carrying a mutation in Pygo2 that strongly reduces its binding to Bcl9/9l2016In: Matters Select, ISSN 2297-9239Article in journal (Refereed)
    Abstract [en]

    Pygopus is a transcriptional activator important for the Wnt signaling pathway. It binds to the beta-catenin transcriptional complex via the adaptor proteins Bcl9 and Bcl9l (Bcl9/9l). This complex is considered to be a suitable target for the treatment of tumors that display activated Wnt signaling. In the mouse, there are two Pygopus-encoding genes, Pygo1 and Pygo2 (Pygo1/2), with the latter playing a major role. Here we introduce a single amino acid substitution in Pygo2, which was previously shown to abrogate binding to Bcl9/9l, and cause lethality in Drosophila melanogaster. We confirm that mutant Pygo2 protein fails in interacting with Bcl9 but, unexpectedly, homozygous mice with this mutation are viable and fertile, even when this mutant allele is combined with a null mutation of the potentially redundant Pygo1. Based on this observation, we conjecture that the Pygo-Bcl9/9l interaction requires scant affinity in vivo to fulfill developmental functions and thrust forward the notion that this interaction surface could be targeted in cancer therapy without major consequences on homeostatic functions.

  • 33.
    Valenta, Tomas
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Degirmenci, Bahar
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Moor, Andreas E
    Department of Molecular Cell Biology, Wolfson Building 623, Weizmann Institute of Science, Rehovot 76100, Israel.
    Herr, Patrick
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Moor, Matthias B
    Department of Pharmacology and Toxicology, University of Lausanne, 1005 Lausanne, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, 1015 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Winterthurerstr. 190, 8057 Zurich, Switzerland.
    Wnt Ligands Secreted by Subepithelial Mesenchymal Cells Are Essential for the Survival of Intestinal Stem Cells and Gut Homeostasis2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 15, no 5, p. 911-918, article id S2211-1247(16)30394-1Article in journal (Refereed)
    Abstract [en]

    Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/β-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/β-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive.

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  • 34.
    Moor, Andreas E.
    et al.
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Anderle, Pascale
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Rodriguez, Patrick
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Wiedemann, Norbert
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Baruthio, Frédérique
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Deka, Jürgen
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    André, Sylvie
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Moor, Matthias B
    Department of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland.
    Győrffy, Balázs
    MTA TTK Lendület Cancer Biomarker Research Group, 2nd Dept. of Pediatrics, Semmelweis University, Budapest, Hungary.
    Barras, David
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.
    Delorenzi, Mauro
    SIB Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, CH-1066 Lausanne, Switzerland; Oncology Department, University of Lausanne, CH-1015 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, Universität Zürich, CH-8057 Zürich, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research (ISREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), School of Life Sciences, CH-1015 Lausanne, Switzerland.
    BCL9/9L-β-catenin Signaling is Associated With Poor Outcome in Colorectal Cancer2015In: EBioMedicine, E-ISSN 2352-3964, Vol. 2, no 12, p. 1932-1943Article in journal (Refereed)
    Abstract [en]

    BCL9/9L proteins enhance the transcriptional output of the β-catenin/TCF transcriptional complex and contribute critically to upholding the high WNT signaling level required for stemness maintenance in the intestinal epithelium. Here we show that a BCL9/9L-dependent gene signature derived from independent mouse colorectal cancer (CRC) models unprecedentedly separates patient subgroups with regard to progression free and overall survival. We found that this effect was by and large attributable to stemness related gene sets. Remarkably, this signature proved associated with recently described poor prognosis CRC subtypes exhibiting high stemness and/or epithelial-to-mesenchymal transition (EMT) traits. Consistent with the notion that high WNT signaling is required for stemness maintenance, ablating Bcl9/9l-β-catenin in murine oncogenic intestinal organoids provoked their differentiation and completely abrogated their tumorigenicity, while not affecting their proliferation. Therapeutic strategies aimed at targeting WNT responses may be limited by intestinal toxicity. Our findings suggest that attenuating WNT signaling to an extent that affects stemness maintenance without disturbing intestinal renewal might be well tolerated and prove sufficient to reduce CRC recurrence and dramatically improve disease outcome.

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  • 35.
    Draganova, Kalina
    et al.
    Cell and Developmental Biology Division, Institute of Anatomy, University of Zurich, Switzerland.
    Zemke, Martina
    Cell and Developmental Biology Division, Institute of Anatomy, Zurich, University of Zurich,Zurich, Switzerland.
    Zurkirchen, Luis
    Cell and Developmental Biology Division, Institute of Anatomy, Zurich, University of Zurich,Zurich, Switzerland.
    Valenta, Tomas
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Cantù, Claudio
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Okoniewski, Michal
    Functional Genomics Center, University of Zurich,Zurich, Switzerland.
    Schmid, Marie-Theres
    Institute for Stem Cell Research, Helmholtz Centre Munich, German Research Center for Environmental Health(GmbH), Neuherberg, Munich, Germany.
    Hoffmans, Raymond
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Götz, Magdalena
    Institute for Stem Cell Research, Helmholtz Centre Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Munich, Physiological Genomics, Institute of Physiology, Ludwig-Maximilians University Munich, Cluster for Systems Neurology (SyNergy), Munich, Germany.
    Basler, Konrad
    Institute ofMolecular Life Sciences, Zurich, University of Zurich,Zurich, Switzerland.
    Sommer, Lukas
    Cell and Developmental Biology Division, Institute of Anatomy, University of Zurich, Switzerland.
    Wnt/β‐Catenin Signaling Regulates Sequential Fate Decisions of Murine Cortical Precursor Cells2015In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 33, no 1, p. 170-182Article in journal (Refereed)
    Abstract [en]

    The fate of neural progenitor cells (NPCs) is determined by a complex interplay of intrinsic programs and extrinsic signals, very few of which are known. β-Catenin transduces extracellular Wnt signals, but also maintains adherens junctions integrity. Here, we identify for the first time the contribution of β-catenin transcriptional activity as opposed to its adhesion role in the development of the cerebral cortex by combining a novel β-catenin mutant allele with conditional inactivation approaches. Wnt/β-catenin signaling ablation leads to premature NPC differentiation, but, in addition, to a change in progenitor cell cycle kinetics and an increase in basally dividing progenitors. Interestingly, Wnt/β-catenin signaling affects the sequential fate switch of progenitors, leading to a shortened neurogenic period with decreased number of both deep and upper-layer neurons and later, to precocious astrogenesis. Indeed, a genome-wide analysis highlighted the premature activation of a corticogenesis differentiation program in the Wnt/β-catenin signaling-ablated cortex. Thus, β-catenin signaling controls the expression of a set of genes that appear to act downstream of canonical Wnt signaling to regulate the stage-specific production of appropriate progenitor numbers, neuronal subpopulations, and astroglia in the forebrain.

  • 36.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Zimmerli, Dario
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Hausmann, George
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Moor, Andreas
    Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 1011 Lausanne, Switzerland.
    Aguet, Michel
    Swiss Institute for Experimental Cancer Research, Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, 1011 Lausanne, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland.
    Pax6-dependent, but β-catenin-independent, function of Bcl9 proteins in mouse lens development.2014In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 28, no 17, p. 1879-84Article in journal (Refereed)
    Abstract [en]

    Bcl9 and Bcl9l (Bcl9/9l) encode Wnt signaling components that mediate the interaction between β-catenin and Pygopus (Pygo) via two evolutionarily conserved domains, HD1 and HD2, respectively. We generated mouse strains lacking these domains to probe the β-catenin-dependent and β-catenin-independent roles of Bcl9/9l and Pygo during mouse development. While lens development is critically dependent on the presence of the HD1 domain, it is not affected by the lack of the HD2 domain, indicating that Bcl9/9l act in this context in a β-catenin-independent manner. Furthermore, we uncover a new regulatory circuit in which Pax6, the master regulator of eye development, directly activates Bcl9/9l transcription.

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  • 37.
    Azim, Kasum
    et al.
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Fischer, Bruno
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Hurtado-Chong, Anahi
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland.
    Draganova, Kalina
    Institute of Anatomy, University of Zürich, Switzerland.
    Cantù, Claudio
    Institute of Molecular Life Sciences, University of Zürich, Switzerland.
    Zemke, Martina
    Institute of Anatomy, University of Zürich, Switzerland.
    Sommer, Lukas
    Institute of Anatomy, University of Zürich, Switzerland.
    Butt, Arthur
    Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biomedical Sciences, Portsmouth University, United Kingdom.
    Raineteau, Olivier
    Brain Research Institute, University of Zürich/ETHZ, Zürich, Switzerland / Stem Cell and Brain Research Institute, INSERMU846, Lyon, France, Universite de Lyon,Universite Lyon, France.
    Persistent Wnt/β‐Catenin Signaling Determines Dorsalization of the Postnatal Subventricular Zone and Neural Stem Cell Specification into Oligodendrocytes and Glutamatergic Neurons2014In: Stem Cells, ISSN 1066-5099, E-ISSN 1549-4918, Vol. 32, no 5, p. 1301-1312Article in journal (Refereed)
    Abstract [en]

    In the postnatal and adult central nervous system (CNS), the subventricular zone (SVZ) of the forebrain is the main source of neural stem cells (NSCs) that generate olfactory neurons and oligodendrocytes (OLs), the myelinating cells of the CNS. Here, we provide evidence of a primary role for canonical Wnt/β-catenin signaling in regulating NSC fate along neuronal and oligodendroglial lineages in the postnatal SVZ. Our findings demonstrate that glutamatergic neuronal precursors (NPs) and oligodendrocyte precursors (OPs) are derived strictly from the dorsal SVZ (dSVZ) microdomain under the control of Wnt/β-catenin, whereas GABAergic NPs are derived mainly from the lateral SVZ (lSVZ) microdomain independent of Wnt/β-catenin. Transcript analysis of microdissected SVZ microdomains revealed that canonical Wnt/β-catenin signaling was more pronounced in the dSVZ microdomain. This was confirmed using the β-catenin-activated Wnt-reporter mouse and by pharmacological stimulation of Wnt/β-catenin by infusion of the specific glycogen synthase kinase 3β inhibitor, AR-A014418, which profoundly increased the generation of cycling cells. In vivo genetic/pharmacological stimulation or inhibition of Wnt/β-catenin, respectively, increased and decreased the differentiation of dSVZ-NSCs into glutamatergic NPs, and had a converse effect on GABAergic NPs. Activation of Wnt/β-catenin dramatically stimulated the generation of OPs, but its inhibition had no effect, indicating other factors act in concert with Wnt/β-catenin to fine tune oligodendrogliogenesis in the postnatal dSVZ. These results demonstrate a role for Wnt/β-catenin signaling within the dorsal microdomain of the postnatal SVZ, in regulating the genesis of glutamatergic neurons and OLs.

  • 38.
    Cantù, Claudio
    et al.
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    Valenta, Tomas
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    Basler, Konrad
    Institute of Molecular Life Sciences, University of Zurich, Switzerland.
    A RING finger to wed TCF and β-catenin2013In: EMBO Reports, ISSN 1469-221X, E-ISSN 1469-3178, Vol. 14, no 4, p. 295-296Article in journal (Refereed)
  • 39.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Bosè, Francesca
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy / Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Bianchi, Paola
    Haematology Unit 2, Unit of Physiopathology of Anaemia, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Reali, Eva
    Department of Immunology, INGM-National Institute of Molecular Genetics, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Barbarani, Gloria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Witke, Walter
    Institut of Genetics, University of Bonn, Bonn, Germany.
    Spinardi, Laura
    Scientific Direction, Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico, Milan, Italy.
    Ronchi, Antonella Ellena
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan Italy.
    Defective Erythroid Maturation In Gelsolin Mutant Mice2012In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 97, no 7, p. 980-988Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: During late differentiation, erythroid cells undergo profound changes involving actin filament remodeling. One of the proteins controlling actin dynamics is gelsolin, a calcium-activated actin filament severing and capping protein. Gelsolin-null (Gsn(-/-)) mice generated in a C57BL/6 background are viable and fertile.1

    DESIGN AND METHODS: We analyzed the functional roles of gelsolin in erythropoiesis by: (i) evaluating gelsolin expression in murine fetal liver cells at different stages of erythroid differentiation (using reverse transcription polymerase chain reaction analysis and immunohistochemistry), and (ii) characterizing embryonic and adult erythropoiesis in Gsn(-/-) BALB/c mice (morphology and erythroid cultures).

    RESULTS: In the context of a BALB/c background, the Gsn(-/-) mutation causes embryonic death. Gsn(-/-) embryos show defective erythroid maturation with persistence of circulating nucleated cells. The few Gsn(-/-) mice reaching adulthood fail to recover from phenylhydrazine-induced acute anemia, revealing an impaired response to stress erythropoiesis. In in vitro differentiation assays, E13.5 fetal liver Gsn(-/-) cells failed to undergo terminal maturation, a defect partially rescued by Cytochalasin D, and mimicked by administration of Jasplakinolide to the wild-type control samples.

    CONCLUSIONS: In BALB/c mice, gelsolin deficiency alters the equilibrium between erythrocyte actin polymerization and depolymerization, causing impaired terminal maturation. We suggest a non-redundant role for gelsolin in terminal erythroid differentiation, possibly contributing to the Gsn(-/-) mice lethality observed in mid-gestation.

  • 40.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Grande, Vito
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Alborelli, Ilaria
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Cassinelli, Letizia
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Cantù, Ileana
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Colzani, Maria Teresa
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Ierardi, Rossella
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, 20132 Milan, Italy.
    Ronzoni, Luisa
    Dipartimento di Medicina Interna, Università di Milano, Fondazione Policlinico Mangiagalli, Regina Elena, IRCCS, Milano, Italy.
    Cappellini, Maria Domenica
    Dipartimento di Medicina Interna, Università di Milano, Fondazione Policlinico Mangiagalli, Regina Elena, IRCCS, Milano, Italy.
    Ferrari, Giuliana
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, 20132 Milan // Vita-Salute San Raffaele University, Milan, Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    Ronchi, Antonella
    Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milan, Italy.
    A highly conserved SOX6 double binding site mediates SOX6 gene downregulation in erythroid cells2011In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 2, p. 486-501Article in journal (Refereed)
    Abstract [en]

    The Sox6 transcription factor plays critical roles in various cell types, including erythroid cells. Sox6-deficient mice are anemic due to impaired red cell maturation and show inappropriate globin gene expression in definitive erythrocytes. To identify new Sox6 target genes in erythroid cells, we used the known repressive double Sox6 consensus within the εy-globin promoter to perform a bioinformatic genome-wide search for similar, evolutionarily conserved motifs located within genes whose expression changes during erythropoiesis. We found a highly conserved Sox6 consensus within the Sox6 human gene promoter itself. This sequence is bound by Sox6 in vitro and in vivo, and mediates transcriptional repression in transient transfections in human erythroleukemic K562 cells and in primary erythroblasts. The binding of a lentiviral transduced Sox6FLAG protein to the endogenous Sox6 promoter is accompanied, in erythroid cells, by strong downregulation of the endogenous Sox6 transcript and by decreased in vivo chromatin accessibility of this region to the PstI restriction enzyme. These observations suggest that the negative Sox6 autoregulation, mediated by the double Sox6 binding site within its own promoter, may be relevant to control the Sox6 transcriptional downregulation that we observe in human erythroid cultures and in mouse bone marrow cells in late erythroid maturation.

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  • 41.
    Cantù, Claudio
    et al.
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ierardi, Rossella
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy.
    Alborelli, Ilaria
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Fugazza, Cristina
    John Radcliffe Hospital, Molecular Hematology Unit, Oxford, United Kingdom.
    Cassinelli, Letizia
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Piconese, Silvia
    Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
    Bosè, Francesca
    5INGM-Fondazione Istituto Nazionale di Genetica molecolare, Milano, Italy.
    Ottolenghi, Sergio
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Ferrari, Giuliana
    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), San Raffaele Scientific Institute, Milano, Italy / Universita` Vita-Salute San Raffaele, Milano, Italy.
    Ronchi, Antonella
    Dipartimento di Biotecnologie e Bioscienze, Universita` di Milano-Bicocca, Milano, Italy.
    Sox6 enhances erythroid differentiation in human erythroid progenitors.2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, no 13, p. 3669-79Article in journal (Refereed)
    Abstract [en]

    Sox6 belongs to the Sry (sex-determining region Y)-related high-mobility-group-box family of transcription factors, which control cell-fate specification of many cell types. Here, we explored the role of Sox6 in human erythropoiesis by its overexpression both in the erythroleukemic K562 cell line and in primary erythroid cultures from human cord blood CD34+ cells. Sox6 induced significant erythroid differentiation in both models. K562 cells underwent hemoglobinization and, despite their leukemic origin, died within 9 days after transduction; primary erythroid cultures accelerated their kinetics of erythroid maturation and increased the number of cells that reached the final enucleation step. Searching for direct Sox6 targets, we found SOCS3 (suppressor of cytokine signaling-3), a known mediator of cytokine response. Sox6 was bound in vitro and in vivo to an evolutionarily conserved regulatory SOCS3 element, which induced transcriptional activation. SOCS3 overexpression in K562 cells and in primary erythroid cells recapitulated the growth inhibition induced by Sox6, which demonstrates that SOCS3 is a relevant Sox6 effector.

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