Anton Wutz

ETH Zurich, Zürich, ZH, Switzerland

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Publications (71)838.62 Total impact

  • Anton Wutz
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    ABSTRACT: Most animal genomes are diploid, and mammalian development depends on specific adaptations that have evolved secondary to diploidy. Genomic imprinting and dosage compensation restrict haploid development to early embryos. Recently, haploid mammalian development has been reinvestigated since the establishment of haploid embryonic stem cells (ESCs) from mouse embryos. Haploid cells possess one copy of each gene, facilitating the generation of loss-of-function mutations in a single step. Recessive mutations can then be assessed in forward genetic screens. Applications of haploid mammalian cell systems in screens have been illustrated in several recent publications. Haploid ESCs are characterized by a wide developmental potential and can contribute to chimeric embryos and mice. Different strategies for introducing genetic modifications from haploid ESCs into the mouse germline have been further developed. Haploid ESCs therefore introduce new possibilities in mammalian genetics and could offer an unprecedented tool for genome exploration in the future.
    Annual Review of Cell and Developmental Biology 10/2014; 30:705-22. · 17.98 Impact Factor
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    ABSTRACT: During X chromosome inactivation (XCI), the Polycomb Repressive Complex 2 (PRC2) is thought to participate in the early maintenance of the inactive state. Although Xist RNA is essential for the recruitment of PRC2 to the X chromosome, the precise mechanism remains unclear. Here, we demonstrate that the PRC2 cofactor Jarid2 is an important mediator of Xist-induced PRC2 targeting. The region containing the conserved B and F repeats of Xist is critical for Jarid2 recruitment via its unique N-terminal domain. Xist-induced Jarid2 recruitment occurs chromosome-wide independently of a functional PRC2 complex, unlike at other parts of the genome, such as CG-rich regions, where Jarid2 and PRC2 binding are interdependent. Conversely, we show that Jarid2 loss prevents efficient PRC2 and H3K27me3 enrichment to Xist-coated chromatin. Jarid2 thus represents an important intermediate between PRC2 and Xist RNA for the initial targeting of the PRC2 complex to the X chromosome during onset of XCI.
    Molecular cell 01/2014; 53(2):301-16. · 14.61 Impact Factor
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    Martin Leeb, Anton Wutz
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    ABSTRACT: Sequencing projects have revealed the information of many animal genomes and thereby enabled the exploration of genome evolution. Insights into how genomes have been repeatedly modified provide a basis for understanding evolutionary innovation and the ever increasing complexity of animal developmental programs. Animal genomes are diploid in most cases, suggesting that redundant information in two copies of the genome increases evolutionary fitness. Genomes are well adapted to a diploid state. Changes of ploidy can be accommodated early in development but they rarely permit successful development into adulthood. In mammals, epigenetic mechanisms including imprinting and X inactivation restrict haploid development. These restrictions are relaxed in an early phase of development suggesting that dosage regulation appears less critical. Here we review the recent literature on haploid genomes and dosage effects and try to embed recent findings in an evolutionary perspective.
    Epigenetics & Chromatin 12/2013; 6(1):41. · 4.19 Impact Factor
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    ABSTRACT: Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin-DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin-DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.
    Nature 08/2013; · 38.60 Impact Factor
  • Anton Wutz
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    ABSTRACT: Spreading of dosage compensation over the X chromosome in Drosophila males requires the noncoding roX1 and roX2 RNAs. In this issue, Ilik et al. (2013) and Maenner et al. (2013) show that these RNAs contain discrete binding sites that are remodeled during assembly of the dosage compensation complex.
    Molecular cell 07/2013; 51(2):131-2. · 14.61 Impact Factor
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    ABSTRACT: Tumor progression is associated with invasiveness and metastatic potential. The special AT-rich binding protein 1 (SATB1) has been identified as a key factor in the progression of breast cancer cells to a malignant phenotype and is associated with progression of human tumors. In normal development, SATB1 coordinates gene expression of progenitor cells by functioning as a genome organizer. In contrast to progenitor and tumor cells, SATB1 expression in nontransformed cells is not compatible with proliferation. Here we show that SATB1 expression in mouse embryonic fibroblasts induces cell cycle arrest and senescence that is associated with elevated p16 protein levels. Deletion of p16 overcomes the SATB1-induced senescence. We further provide evidence for an interaction of SATB1 with the retinoblastoma (RB)/E2F pathway downstream of p16. A combined deletion of the RB proteins, RB, p107 and p130 (triple-mutant; TM), prevents SATB1-induced G1 arrest, which is restored upon the reintroduction of RB into SATB1-expressing TM fibroblasts. SATB1 interacts with the E2F/RB complex and regulates the cyclin E promoter in an E2F-dependent manner. These findings demonstrate that p16 and the RB/E2F pathway are critical for SATB1-induced cell cycle arrest. In the absence of p16, SATB1 causes anchorage-independent growth and invasive phenotype in fibroblasts. Our data illustrate that p16 mutations collaborate with the oncogenic activity of SATB1. Consistent with our finding, a literature survey shows that deletion of p16 is generally associated with SATB1 expressing human cell lines and tumors.Oncogene advance online publication, 20 May 2013; doi:10.1038/onc.2013.158.
    Oncogene 05/2013; · 8.56 Impact Factor
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    ABSTRACT: BACKGROUND: Histone deacetylase inhibitors (HDACi) cause histone hyperacetylation and H3K4 hypermethylation in various cell types. They find clinical application as anti-epileptics and chemotherapeutic agents, but the pathways through which they operate remain unclear. Surprisingly, changes in gene expression caused by HDACi are often limited in extent and can be positive or negative. Here we have explored the ability of the clinically important HDACi valproic acid (VPA) to alter histone modification and gene expression, both globally and at specific genes, in mouse embryonic stem (ES) cells. RESULTS: Microarray expression analysis of ES cells exposed to VPA (1 mM, 8 h), showed that only 2.4% of genes showed a significant, >1.5-fold transcriptional change. Of these, 33% were down-regulated. There was no correlation between gene expression and VPA-induced changes in histone acetylation or H3K4 methylation at gene promoters, which were usually minimal. In contrast, all Hoxb genes showed increased levels of H3K9ac after exposure to VPA, but much less change in other modifications showing bulk increases. VPA-induced changes were lost within 24 h of inhibitor removal. VPA significantly increased the low transcription of Hoxb4 and Hoxb7, but not other Hoxb genes. Expression of Hoxb genes increased in ES cells lacking functional Polycomb silencing complexes PRC1 and PRC2. Surprisingly, VPA caused no further increase in Hoxb transcription in these cells, except for Hoxb1, whose expression increased several fold. Retinoic acid (RA) increased transcription of all Hoxb genes in differentiating ES cells within 24 h, but thereafter transcription remained the same, increased progressively or fell progressively in a locus-specific manner. CONCLUSIONS: Hoxb genes in ES cells are unusual in being sensitive to VPA, with effects on both cluster-wide and locus-specific processes. VPA increases H3K9ac at all Hoxb loci but significantly overrides PRC-mediated silencing only at Hoxb4 and Hoxb7. Hoxb1 is the only Hoxb gene that is further up-regulated by VPA in PRC-deficient cells. Our results demonstrate that VPA can exert both cluster-wide and locus-specific effects on Hoxb regulation.
    Epigenetics & Chromatin 05/2013; 6(1):11. · 4.19 Impact Factor
  • Asun Monfort, Anton Wutz
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    ABSTRACT: Vitamin C is an antioxidant that maintains the activity of iron and α-ketoglutarate-dependent dioxygenases. Despite these enzymes being implicated in a wide range of biological pathways, vitamin C is rarely included in common cell culture media. Recent studies show that reprogramming of pluripotent stem cells is enhanced when vitamin C is present, thereby illustrating previous limitations in reprogramming cultures. Here, we summarize understanding of dioxygenase function in reprogramming and epigenetic regulation. The available data suggest a link between dioxygenase function and stem cell differentiation, which is exposed to environmental influence and is relevant for human disease.
    EMBO Reports 03/2013; · 7.19 Impact Factor
  • Christoph Bock, Anton Wutz
    Nature Structural & Molecular Biology 03/2013; 20(3):249-51. · 11.90 Impact Factor
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    Anton Wutz, Martin Leeb
    Epigenetics & Chromatin 03/2013; 6(1). · 4.19 Impact Factor
  • Anton Wutz
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    ABSTRACT: The specialized cell types of tissues and organs are generated during development and are replenished over lifetime though the process of differentiation. During differentiation the characteristics and identity of cells are changed to meet their functional requirements. Differentiated cells then faithfully maintain their characteristic gene expression patterns. On the molecular level transcription factors have a key role in instructing specific gene expression programs. They act together with chromatin regulators which stabilize expression patterns. Current evidence indicates that epigenetic mechanisms are essential for maintaining stable cell identities. Conversely, the disruption of chromatin regulators is associated with disease and cellular transformation. In mammals, a large number of chromatin regulators have been identified. The Polycomb group complexes and the DNA methylation system have been widely studied in development. Other chromatin regulators remain to be explored. This chapter focuses on recent advances in understanding epigenetic regulation in embryonic and adult stem cells in mammals. The available data illustrate that several chromatin regulators control key lineage specific genes. Different epigenetic systems potentially could provide stability and guard against loss or mutation of individual components. Recent experiments also suggest intervals in cell differentiation and development when new epigenetic patterns are established. Epigenetic patterns have been observed to change at a progenitor state after stem cells commit to differentiation. This finding is consistent with a role of epigenetic regulation in stabilizing expression patterns after their establishment by transcription factors. However, the available data also suggest that additional, presently unidentified, chromatin regulatory mechanisms exist. Identification of these mechanism is an important aim for future research to obtain a more complete framework for understanding stem cell differentiation during tissue homeostasis.
    Advances in experimental medicine and biology 01/2013; 786:307-28. · 1.83 Impact Factor
  • Anton Wutz, Ruben Agrelo
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    ABSTRACT: In this issue, Nechanitzky et al. question the role of SATB proteins in conferring cellular competence to respond to Xist. Here, Wutz and Agrelo respond, discussing ways to reconcile the available data. Both groups agree that multiple redundant factors may contribute in parallel.
    Developmental Cell 10/2012; 23(4):680. · 12.86 Impact Factor
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    Tatsuya Ohhata, Anton Wutz
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    ABSTRACT: In mammals, one of the two X chromosomes of female cells is inactivated for dosage compensation between the sexes. X chromosome inactivation is initiated in early embryos by the noncoding Xist RNA. Subsequent chromatin modifications on the inactive X chromosome (Xi) lead to a remarkable stability of gene repression in somatic cell lineages. In mice, reactivation of genes on the Xi accompanies the establishment of pluripotent cells of the female blastocyst and the development of primordial germ cells. Xi reactivation also occurs when pluripotency is established during the reprogramming of somatic cells to induced pluripotent stem cells. The mechanism of Xi reactivation has attracted increasing interest for studying changes in epigenetic patterns and for improving methods of cell reprogramming. Here, we review recent advances in the understanding of Xi reactivation during development and reprogramming and illustrate potential clinical applications.
    Cellular and Molecular Life Sciences CMLS 09/2012; · 5.62 Impact Factor
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    ABSTRACT: Haploid embryonic stem cells (ESCs) have recently been derived from parthenogenetic mouse embryos and offer new possibilities for genetic screens. The ability of haploid ESCs to give rise to a wide range of differentiated cell types in the embryo and in vitro has been demonstrated. However, it has remained unclear whether haploid ESCs can contribute to the germline. Here, we show that parthenogenetic haploid ESCs at high passage have robust germline competence enabling the production of transgenic mouse strains from genetically modified haploid ESCs. We also show that differentiation of haploid ESCs in the embryo correlates with the gain of a diploid karyotype and that diploidisation is the result of endoreduplication and not cell fusion. By contrast, we find that a haploid karyotype is maintained when differentiation to an extra-embryonic fate is forced by induction of Gata6.
    Development 09/2012; 139(18):3301-5. · 6.60 Impact Factor
  • Anton Wutz
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    ABSTRACT: Human somatic cells can be reprogrammed into induced pluripotent stem cells (hiPSCs) with wide lineage differentiation potential in culture. However, reprogramming and long-term culture can also induce abnormalities in these pluripotent cells. This minireview discusses recent studies that have identified changes in imprinted gene expression and erosion of X chromosome inactivation in female hiPSCs and how understanding the sources and consequences of epigenetic variability in hiPSCs will impact disease modeling and clinical application in the future.
    Cell stem cell 07/2012; 11(1):9-15. · 23.56 Impact Factor
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    Martin Leeb, Anton Wutz
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    ABSTRACT: The distinct cell types of the body are established from the fertilized egg in development and assembled into functional tissues. Functional characteristics and gene expression patterns are then faithfully maintained in somatic cell lineages over a lifetime. On the molecular level, transcription factors initiate lineage-specific gene expression programmmes and epigenetic regulation contributes to stabilization of expression patterns. Epigenetic mechanisms are essential for maintaining stable cell identities and their disruption can lead to disease or cellular transformation. Here, we discuss the role of epigenetic regulation in the early mouse embryo, which presents a relatively well-understood system. A number of studies have contributed to the understanding of the function of Polycomb group complexes and the DNA methylation system. The role of many other chromatin regulators in development remains largely unexplored. Albeit the current picture remains incomplete, the view emerges that multiple epigenetic mechanisms cooperate for repressing critical developmental regulators. Some chromatin modifications appear to act in parallel and others might repress the same gene at a different stage of cell differentiation. Studies in pluripotent mouse embryonic stem cells show that epigenetic mechanisms function to repress lineage specific gene expression and prevent extraembryonic differentiation. Insights into this epigenetic "memory" of the first lineage decisions help to provide a better understanding of the function of epigenetic regulation in adult stem cell differentiation.
    Chromosoma 03/2012; 121(3):251-62. · 3.34 Impact Factor
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    ABSTRACT: Polycomb-repressive complex 1 (PRC1) has a central role in the regulation of heritable gene silencing during differentiation and development. PRC1 recruitment is generally attributed to interaction of the chromodomain of the core protein Polycomb with trimethyl histone H3K27 (H3K27me3), catalyzed by a second complex, PRC2. Unexpectedly we find that RING1B, the catalytic subunit of PRC1, and associated monoubiquitylation of histone H2A are targeted to closely overlapping sites in wild-type and PRC2-deficient mouse embryonic stem cells (mESCs), demonstrating an H3K27me3-independent pathway for recruitment of PRC1 activity. We show that this pathway is mediated by RYBP-PRC1, a complex comprising catalytic subunits of PRC1 and the protein RYBP. RYBP-PRC1 is recruited to target loci in mESCs and is also involved in Xist RNA-mediated silencing, the latter suggesting a wider role in Polycomb silencing. We discuss the implications of these findings for understanding recruitment and function of Polycomb repressors.
    Cell 02/2012; 148(4):664-78. · 31.96 Impact Factor
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    ABSTRACT: Polycomb group proteins are essential regulators of cell fate decisions during embryogenesis. In mammals, at least five different Cbx proteins (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8) are known to associate with the core Polycomb repressive complex 1 (PRC1). Here we show that pluripotency and differentiation of mouse embryonic stem cells (ESCs) is regulated by different Cbx-associated PRC1 complexes with unique functions. Maintenance of pluripotency primarily depends on Cbx7, while lineage commitment is orchestrated by Cbx2 and Cbx4. At the molecular level, we have uncovered a Polycomb autoregulatory loop in which Cbx7 represses the expression of prodifferentiation Cbx proteins, thereby maintaining the pluripotent state. We additionally show that the occupancy of Cbx7 on promoters is completely dependent on PRC2 activity but only partially dependent on a functional PRC1 complex. Thus, Cbx proteins confer distinct target selectivity to the PRC1 complex, achieving a balance between the self-renewal and the differentiation of ESCs.
    Cell stem cell 01/2012; 10(1):47-62. · 23.56 Impact Factor
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    ABSTRACT: X-chromosome inactivation (XCI) in female mammals depends on the noncoding RNA X inactivation specific transcript (Xist). The mechanism of chromosome-wide silencing by Xist is poorly understood. While it is established that the 5' region of Xist RNA, comprising the A-repeats and holding 7.5-8.5 copies of a conserved 26-mer sequence, is essential for Xist-mediated silencing, high-resolution structural information for the A-repeats is not available. Here, we report the three-dimensional solution structure of a 14-mer hairpin in the 5' region of a human A-repeat. This hairpin is remarkably stable and adopts a novel AUCG tetraloop fold, the integrity of which is required for silencing. We show that, contrary to previous predictions, the 3' region of single or tandem A-repeats mediates duplex formation in vitro. Significantly, mutations in this region disrupt the inter-repeat duplex formation in vitro and abrogate the silencing function of Xist A-repeats in vivo. Our data suggest that the complete A-repeat region may be stabilized by inter-repeat duplex formation and, as such, may provide a platform for multimerization and specific recognition of the AUCG tetraloops by trans-acting factors.
    RNA 09/2011; 17(11):1973-82. · 5.09 Impact Factor
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    Martin Leeb, Anton Wutz
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    ABSTRACT: Most animals are diploid, but haploid-only and male-haploid (such as honeybee and ant) species have been described. The diploid genomes of complex organisms limit genetic approaches in biomedical model species such as mice. To overcome this problem, experimental induction of haploidy has been used in fish. Haploid development in zebrafish has been applied for genetic screening. Recently, haploid pluripotent cell lines from medaka fish (Oryzias latipes) have also been established. In contrast, haploidy seems less compatible with development in mammals. Although haploid cells have been observed in egg cylinder stage parthenogenetic mouse embryos, most cells in surviving embryos become diploid. Here we describe haploid mouse embryonic stem cells and show their application in forward genetic screening.
    Nature 09/2011; 479(7371):131-4. · 38.60 Impact Factor

Publication Stats

4k Citations
838.62 Total Impact Points

Institutions

  • 2013
    • ETH Zurich
      • Institute of Molecular Health Sciences
      Zürich, ZH, Switzerland
    • Institut Pasteur de Montevideo
      Ciudad de Montevideo, Montevideo, Uruguay
    • Austrian Academy of Sciences
      Wien, Vienna, Austria
  • 2010–2013
    • University of Cambridge
      • Stem Cell Institute
      Cambridge, England, United Kingdom
    • Wellcome Trust
      Londinium, England, United Kingdom
  • 1997–2011
    • Research Institute of Molecular Pathology
      Wien, Vienna, Austria
  • 2006–2010
    • Institut Curie
      Lutetia Parisorum, Île-de-France, France
  • 2003–2009
    • University of Vienna
      • Institute of Molecular Pathology
      Vienna, Vienna, Austria
  • 2008
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
    • Kanazawa University
      • Department of Stem Cell Biology
      Kanazawa, Ishikawa, Japan
  • 2002
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, MA, United States
  • 1998–2002
    • Whitehead Institute for Biomedical Research
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1998–2001
    • Netherlands Cancer Institute
      • Division of Molecular Genetics
      Amsterdamo, North Holland, Netherlands