Project

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Polycomb and stem cell identity in vitro and in vivo

English title Polycomb and stem cell identity in vitro and in vivo
Applicant Peters Antoine Hendrik Felix Marie
Number 128131
Funding scheme NRP 63 Stem cells and regenerative medicine
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Embryology, Developmental Biology
Start/End 01.11.2010 - 28.02.2015
Approved amount 767'536.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Molecular Biology

Keywords (6)

totipotency; embryonic stem cell; Polycomb group protein; Epigenetic inheritance; Lineage specification; Pre-implantation development

Lay Summary (English)

Lead
Lay summary
How an embryo develops from a sperm and an egg

How does a new cell form in a matter of hours from a sperm and an egg which then develops into a human being? The aim of this research project is to investigate the role of the Polycomb group (PcG) proteins in this fusion process.

Background
The start of a human life is stunning. Two cells, a sperm and an egg, converge to form a new cell which is now in a position to become a human being. The original cells could not achieve that on their own. And unlike the two original cells, the fertilised egg cell is totipotent - all cell types of the human body can develop from it.
The creation of this totipotent cell is extremely complicated and dependent on various factors. The genetic material, the DNA, is involved of course. For example, certain genes, which were active during the creation of sperm and egg are switched off and vice versa. In addition, proteins which surround the DNA are important. The Polycomb group (PcG) proteins play a critical role in this process. These proteins are master regulators of embryo development and growth. They carry out their work by modifying the complex of DNA and proteins, known as chromatin, and by steering the activity of genes. However, the exact mode of action is largely unknown.

Aim
The aim of this research project is to investigate the role that PcG proteins play in the fusion of sperm and egg and the creation of totipotent embryos.

Significance
The project should shed new light on the formation and regulation of embryonic stem cells. Because similar processes are involved in the production of artificially derived pluripotent stem cells known as iPS cells, there are potential implications for the production of iPS cells (iPS means induced pluripotent stem cells).


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Cbx2 Targets PRC1 to Constitutive Heterochromatin in Mouse Zygotes in a Parent-of-Origin-Dependent Manner.
Tardat Mathieu, Albert Mareike, Kunzmann Rico, Liu Zichuan, Kaustov Lilia, Thierry Raphael, Duan Shili, Brykczynska Urszula, Arrowsmith Cheryl H, Peters Antoine H F M (2015), Cbx2 Targets PRC1 to Constitutive Heterochromatin in Mouse Zygotes in a Parent-of-Origin-Dependent Manner., in Molecular cell, 58(1), 157-71.
Genome-wide chromatin analysis in mature mouse and human spermatozoa.
Hisano Mizue, Erkek Serap, Dessus-Babus Sophie, Ramos Liliana, Stadler Michael B, Peters Antoine H F M (2013), Genome-wide chromatin analysis in mature mouse and human spermatozoa., in Nature protocols, 8(12), 2449-70.
H3K9/HP1 and Polycomb: two key epigenetic silencing pathways for gene regulation and embryo development.
Nestorov Peter, Tardat Mathieu, Peters Antoine H F M (2013), H3K9/HP1 and Polycomb: two key epigenetic silencing pathways for gene regulation and embryo development., in Current topics in developmental biology, 104, 243-91.
Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa.
Erkek Serap, Hisano Mizue, Liang Ching-Yeu, Gill Mark, Murr Rabih, Dieker Jürgen, Schübeler Dirk, van der Vlag Johan, Stadler Michael B, Peters Antoine H F M (2013), Molecular determinants of nucleosome retention at CpG-rich sequences in mouse spermatozoa., in Nature structural & molecular biology, 20(7), 868-75.
PRC1 coordinates timing of sexual differentiation of female primordial germ cells.
Yokobayashi Shihori, Liang Ching-Yeu, Kohler Hubertus, Nestorov Peter, Liu Zichuan, Vidal Miguel, van Lohuizen Maarten, Roloff Tim C, Peters Antoine H F M (2013), PRC1 coordinates timing of sexual differentiation of female primordial germ cells., in Nature, 495(7440), 236-40.
[Crucial role of Polycomb proteins from maternal origin in mouse early embryonic development].
Salvaing Juliette, Posfai Eszter, Peters Antoine H F M, Beaujean Nathalie (2012), [Crucial role of Polycomb proteins from maternal origin in mouse early embryonic development]., in Médecine sciences : M/S, 28(12), 1047-9.
Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?
Gill Mark E, Erkek Serap, Peters Antoine H F M (2012), Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?, in Current opinion in cell biology, 24(3), 387-96.
Polycomb function during oogenesis is required for mouse embryonic development.
Posfai Eszter, Kunzmann Rico, Brochard Vincent, Salvaing Juliette, Cabuy Erik, Roloff Tim C, Liu Zichuan, Tardat Mathieu, van Lohuizen Maarten, Vidal Miguel, Beaujean Nathalie, Peters Antoine H F M (2012), Polycomb function during oogenesis is required for mouse embryonic development., in Genes & development, 26(9), 920-32.

Collaboration

Group / person Country
Types of collaboration
Haruhiko Koseki / Riken Japan (Asia)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Seminar at Molecular Health Sciences Platform, ETH Zürich Individual talk Chromatin inheritance and dynamics at the onset of life: mechanisms and functional implications 27.03.2015 Zurich, Switzerland Peters Antoine Hendrik Felix Marie;
SyBoSS 2015 Double Conference: Program of Early Mammalian Development & Systems Biology of Stem Cells Talk given at a conference Chromatin inheritance and dynamics at the onset of life: mechanisms and functional implications 07.03.2015 Oberstdorf, Germany Peters Antoine Hendrik Felix Marie; Ozonov Evgeniy;
Seminar at the University of Kyoto Individual talk Epigenetic control of mammalian germ line and early embryonic development 28.11.2014 Kyoto, Japan Peters Antoine Hendrik Felix Marie;
The 37th Annual Meeting of the Molecular Biology Society of Japan Talk given at a conference Epigenetic control of mammalian germ line and early embryonic development 26.11.2014 Yokohama, Japan Peters Antoine Hendrik Felix Marie;
Seminar at the RIKEN Center for Integrative Medical Sciences Individual talk Epigenetic control of mammalian germ line and early embryonic development 25.11.2014 Yokohama, Japan Peters Antoine Hendrik Felix Marie;
GRC meeting on Mammalian Reproduction, Talk given at a conference Formation and function of constitutive heterochromatin in early mouse embryos 11.08.2014 Colby-Sawyer College, New London, NH, United States of America Peters Antoine Hendrik Felix Marie;
EpiGenMed workshop “Epigenome regulation in development and disease”, Montpellier, France Talk given at a conference Formation and function of constitutive heterochromatin in early mouse embryos 04.07.2014 Montpellier, France Peters Antoine Hendrik Felix Marie;
Keystone Symposia meeting on Epigenetic Programming and Inheritance Talk given at a conference Epigenetic control of mouse germ cell and early embryonic development 07.04.2014 Boston, United States of America Peters Antoine Hendrik Felix Marie;
International Meeting of the German Society of Cell Biology Talk given at a conference Epigenetic control of mouse germ cell and early embryonic development 20.03.2014 Regensburg, Germany Peters Antoine Hendrik Felix Marie;
EPICONCEPT Epigenetics and Periconception meeting: “ Epigenetics for Improved Food Production: from Model to Practice“ Talk given at a conference Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming? 13.10.2013 Sant Feliu de Guíxols, Spain Peters Antoine Hendrik Felix Marie;
Chromatin and Systems Biology Spetses Summer School Talk given at a conference Epigenetic control of mammalian germ line and early embryonic development 01.09.2013 Spetses island, Greece Peters Antoine Hendrik Felix Marie;
XXII North American Testis Workshop: “The Foundations of Male Fertility” Talk given at a conference Towards understanding the molecular logic of paternal epigenetic inheritance 10.04.2013 San Antonio, United States of America Peters Antoine Hendrik Felix Marie;
5th Annual Symposium of the Réseau Québécois en Reproduction Talk given at a conference Epigenetic control of mammalian germ line and early embryonic development 15.11.2012 Quebec, Canada Peters Antoine Hendrik Felix Marie;
Protein-Kompetenznetzwerk-Halle, ProNet-T3, Germany Talk given at a conference Epigenetic Control of Mammalian Germ Line and Early Embryonic Development 27.09.2012 Halle, Germany Peters Antoine Hendrik Felix Marie;


Communication with the public

Communication Title Media Place Year
Media relations: print media, online media Detailing heterochromatin formation at the onset of life FMI website International 2015

Awards

Title Year
EMBO Membership 2014

Abstract

BackgroundMammalian development starts by fusion of two highly differentiated germ cells and formation of the totipotent embryo. Mouse embryonic stem cells (ESCs) are pluripotent cells that can be derived from pre-implantation embryos at different stages of their development. In ESCs, cell identity is primarily regulated by transcription factors, e.g. Oct3/4, Sox2, and Nanog that are considered master regulators of pluripotency in vivo and in vitro and share many target genes. Gene transcription occurs, however, in the context of chromatin that serves either potentiating or restricting functions. As such, chromatin-based mechanisms contribute to the translation of genetic information. A large number of studies have shown that chromatin modifiers play a conserved role in the heritability of cell identity during somatic differentiation and in safeguarding genome stability. Since such transmission of information occurs in absence of changes in the underlying genetic code, this type of inheritance is referred to as “epigenetic”. Polycomb group (PcG) proteins are evolutionarily conserved chromatin factors that mediate gene repression. In mammals, they function in at least two different multi-protein complexes, called Polycomb Repressive Complex (PRC) 1 and 2, that mediate mono-ubiquitination of H2A at lysine 119 (H2AK119u1) and H3K27me3 respectively. These complexes typically repress genes with key regulatory functions in development and differentiation. Double-deficiency for the PRC1 paralogues, Ring1b/Rnf2 and Ring1a, causes a loss of ESC identity. Similarly, double deficiency for the core PRC1 components Ring1a and Ring1b/Rnf2 causes a developmental arrest around the eight-cell stage (unpublished data). Thus, as in ESCs, PRC1 function seems to be required for the development of totipotency during early embryogenesis. This grant application focuses on the targeting mechanisms of the PRC1 and their role in regulating cell identity of ESCs. In particular, it proposes to study the function of a family of Cbx proteins, components of PRC1, for targeting of PRC1 to chromatin and possibly specific sets of genes. These proteins contain a chromo domain that has affinity for methylated histones. The work proposed will assess to function of these chromo domains for PRC1 targeting. Furthermore, it concentrates on PRC1 function during early embryogenesis at the time of the first and second lineage decisions that ultimately give rise to the pluripotent inner cell mass and the two differentiation lineages (trophectoderm and primitive endoderm).Hypotheses1: We propose that the five different Cbx proteins contribute to target selection and specification of cell identity. We put forward that target specification is mediated, in part, by the CD of the different Cbx proteins. Furthermore, we propose that Cbx2 functions to inhibit binding of PRC1 complexes to H3K9 methylated chromatin, thereby contributing to partitioning of mammalian genomes ac-cording to epigenetic states.2: We hypothesize that the PRC1 complex and its component Cbx2 play important roles in regulating gene expression in early embryos, during the so-called maternal-to-zygotic transition in which transcription becomes activated in a largely genome-wide manner and during subsequent lineage specification. Cbx7 may be important for embryonic development towards the blastocyst stage.To investigate these hypotheses, we propose the following aims:1: To investigate the role of Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8 in specifying PRC1 targeting and cell identity of undifferentiated and differentiating embryonic stem cells. 2: To assess the role of chromo domains of Cbx proteins in chromatin targeting of PRC1. 3: To determine the function of PRC1 and Cbx proteins in early embryogenesisPossible applicationsThe proposed work represents a systematic approach to dissect the mechanisms of transcriptional control by Polycomb group proteins in regulating cell identity of embryonic stem cells and during pre-implantation development. The anticipated results will provide insights into the controlling of transcriptional networks functioning in early embryos that direct the acquisition of totipotency (early stages) and drive differentiation into the first cellular lineages (later stage embryos). The mechanistic understanding obtained in these in vitro and vivo studies will aid the elucidation of epigenetic reprogramming mechanisms implicated in the generation of induced pluripotent stem (iPS) cells in vitro. As such, this work is expected to significantly contribute to studies on reprogramming of differentiated cells for therapeutic usage.
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