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EPIGENETIC CONTROL OF EARLY MOUSE DEVELOPMENT

English title EPIGENETIC CONTROL OF EARLY MOUSE DEVELOPMENT
Applicant Peters Antoine Hendrik Felix Marie
Number 125386
Funding scheme Project funding (Div. I-III)
Research institution Friedrich Miescher Institute for Biomedical Research
Institution of higher education Institute Friedrich Miescher - FMI
Main discipline Embryology, Developmental Biology
Start/End 01.04.2009 - 31.03.2012
Approved amount 537'000.00
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All Disciplines (2)

Discipline
Embryology, Developmental Biology
Genetics

Keywords (11)

pre-implantation development; totipotency; parental specific transgenerational inheritance; epigenetics; histone methylation; Polycomb Group proteins; RNA deep-sequencing; systems biology; transgenerational; inheritance; chromatin

Lay Summary (English)

Lead
Lay summary
In eukaryotes, genetic information encoded in DNA is packaged by proteins into a configuration called chromatin. Through the modulation of chromatin, the translation of the genetic code is coordinated. Epigenetic regulators are known as factors that regulate chromatin states and that play an important role in the definition and heritability of cell identity during somatic differentiation. Recent studies showed that certain epigenetic modifiers also regulate the maintenance of the differentiation potential and self-renewal capacity of embryonic stem cells. In contrast, remarkably little is known about the epigenetic mechanisms that regulate the acquisition of totipotency and subsequent lineage specification during very early mammalian development, shortly after fertilization. In mammals, fusion of an oocyte and a spermatozoon, two highly differentiated germ cells, leads to the formation of the totipotent embryo. Epigenetic reprogramming processes occurring during gametogenesis are thought to facilitate efficient re-acquisition of totipotency in early embryos, arguing for an epigenetic transgenerational contribution towards early development. In this project, we study the role of chromatin and their epigenetic regulators in pre-implantation development. Specifically, we pursue the following aims: 1. to characterize the role of distinct epigenetic repressive pathways in the control of zygotic gene activation in early pre-implantation embryos; 2. to assess the functional significance of transgenerational transmission of specific post-translational modifications on chromatin for gene activity or repression in the early embryo; 3. to study the contribution of specific epigenetic modifiers for lineage specification and cellular differentiation during pre-implantation development. We anticipate that the research will provide important insights in the mechanisms of transgenerational inheritance of epigenetic information as well as in the transcriptional and chromatin-based networks that control the acquisition of totipotency and first lineage specification during mammalian embryogenesis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
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.
Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?
Gill Mark E, Erkek Serap, Peters Antoine Hfm (2012), Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?, in Current opinion in cell biology, currently online, ---.
Epigenetics: Tet proteins in the limelight.
Véron Nathalie, Peters Antoine H F M (2011), Epigenetics: Tet proteins in the limelight., in Nature, 473(7347), 293-4.
Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa.
Brykczynska Urszula, Hisano Mizue, Erkek Serap, Ramos Liliana, Oakeley Edward J, Roloff Tim C, Beisel Christian, Schübeler Dirk, Stadler Michael B, Peters Antoine H F M (2010), Repressive and active histone methylation mark distinct promoters in human and mouse spermatozoa., in Nature structural & molecular biology, 17(6), 679-87.
Genetic and epigenetic control of early mouse development.
Albert Mareike, Peters Antoine H F M (2009), Genetic and epigenetic control of early mouse development., in Current opinion in genetics & development, 19(2), 113-21.
Protein demethylation required for DNA methylation.
Hotz Hans-Rudolf, Peters Antoine H F M (2009), Protein demethylation required for DNA methylation., in Nature genetics, 41(1), 10-1.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2nd SKLRB Symposia on Frontiers in Reproductive Biology 06.05.2012 (organized by State Key Laboratory of Reproductive Biology, the Institute of Zoology, Chinese Academ
4th EMBO conference on "Nuclear Structure and Dynamics", 28.09.2011 L'Isle de la Sorgue, France (speaker and session chair)
Max-Delbrück-Center Conference on “Stem Cells in Development and Disease”, 10.09.2011 Berlin, Germany
Gordon Research Conference on “Mammalian Gametogenesis and Embryogenesis” 21.08.2011 Waterville Valley, NH, USA
1st CSCR Annual Symposium on "Pluripotency and Development" 06.07.2011 Wellcome Trust Centre for Stem Cell Research, University of Cambridge, United Kingdom
Invited Seminar to the BC2 Seminar Series in the Biozentrum 11.04.2011 Basel, Switzerland
Invited Seminar for the Seminar Series on Genetics and Development, Institut de Génétique Humaine, 17.03.2011 Montpellier, France
Invited Seminar in the Queenslands Institue of Medical Research 17.02.2011 Brisbane, Australia
32nd Lorne Genome Conference, 13.02.2011 Lorne near Melbourne, Australia
Annual Meeting of the Netherlands Organization for Scientific Research (NWO), 06.12.2010 the Netherlands
PhD student’s symposium on “Changing cell fate, molecular basis and multi-scaled engineering of cell reprogramming” 19.10.2010 Albert Bonniot Institute, Grenoble, France
FMI 40th anniversary symposium on “Frontiers in Biomedical Research” 20.09.2010 Basel, Switzerland
PhD student’s symposium on “Meeting, Pairing and Propagating - the molecular biology of sexual reproduction” 12.09.2010 the Max F. Perutz Laboratories at the University of Vienna, Austria
Young Investigator Meeting on Cancer 14.06.2010 Split, Croatia
10th EMBO Young Investigator Meeting, 10.05.2010 Heidelberg, Germany
Invited Seminar in the Brain Research Institute, ETH Zürich 19.04.2010 Zürich, Switzerland
6th course on Epigenetics, Curie Institute 22.03.2010 Paris, France
Epigenome NoE Conference “Epigenetic Regulation in Cell Fate and Disease”, 17.03.2010 Vienna, Austria
Swiss Stem Cell Network Annual Meeting 05.02.2010 Basel, Switzerland
Swiss Tissue Culture Society workshop “Programming cells for assay development and tissue engineering” 18.11.2009 Basel, Switzerland
Invited Seminar in the Rheumaklinik und Institut für Physikalische Medizin, Univ. Of Zürich 03.11.2009 Zürich, Switzerland
SGC meeting on “Epigenetics in Health and Disease”, 22.10.2009 Toronto, Canada
22nd Annual mouse meeting (CSH): “Mouse Genetics & Genomics: Development and Disease”, 02.09.2009 Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
4th Asian Epigenomics meeting “Epigenetics in Development and Diseases” 24.08.2009 The Biopolis, Singapore
Invited Seminar in the the Jackson Laboratory 23.07.2009 Bar Harbor, ME, USA
Invited Seminar in the Genomics Institute of the Novartis Research Foundation (GNF), 21.07.2009 San Diego, CA, USA
Invited Seminar in the Institute Emory University 20.07.2009 Atlanta GA, USA
Gordon Research Conference "Fertilization and Activation of Development" 12.07.2009 Holderness School, New Hampshire, USA


Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions IN-VITRO ERZEUGT UND SELEKTIERT German-speaking Switzerland 08.01.2012

Associated projects

Number Title Start Funding scheme
146293 Establishment of chromatin states in mouse sperm and their relevance for paternal epigenetic inheritance 01.10.2013 Project funding (Div. I-III)

Abstract

Background: Through the modulation of chromatin states, epigenetic mechanisms contribute to the reading of genetic information. Classically, epigenetic regulators are known to play a conserved role in the heritability of cell identity during somatic differentiation and in genome stability. Recent studies showed that certain epigenetic modifiers regulate the maintenance of differentiation potential and self-renewal capacity in stem cells. In contrast, remarkably little is known about the epigenetic mechanisms regulating the acquisition of totipotency and subsequent lineage specification during early mammalian development. In mammals, fusion of an oocyte and a spermatozoon, two highly differentiated, transcriptionally silent germ cells, leads to the formation of a totipotent embryo. Epigenetic reprogramming processes occurring during gametogenesis are thought to facilitate efficient re-acquisition of totipotency in blastomeres, individual cells within early embryos, arguing for an epigenetic transgenerational contribution. Accordingly, we recently demonstrated a role for transgenerational inheritance of histone lysine methylation in the establishment of proper chromatin states and control of transcriptional repression at constitutive heterochromatin in the early embryo. Furthermore, preliminary data indicate that expression of selected genes in early embryos is regulated by distinct chromatin based repressive pathways. Another recent publication implicated histone arginine methylation in lineage determination during pre-implantation development.Hypotheses: 1.We hypothesize that epigenetic repressive mechanisms control zygotic gene activation in a parent-of-origin dependent manner in early mouse pre-implantation embryos.2.We put forward that transgenerational transmission of histone methylation controls gene specific repression in early embryos.3. We propose that epigenetic mechanisms contribute to lineage specification during mouse pre-implantation development. Aims: To test these hypotheses we propose the following specific aims:1.To investigate the role of distinct epigenetic repressive pathways in the control of zygotic gene activation in early pre-implantation embryos. Towards this goal, we will perform unbiased genome-wide expression analyses by microarray and RNA deep-sequencing methods in early embryos, wild-type or maternally and/or zygotically deficient for one or more histone methyltransferases and Polycomb Group proteins. Candidate genes will be validated by RT-qPCR. We will use DNA polymorphisms to determine the parental origin of alleles. Detection of nascent transcripts by RNA-FISH will be used to differentiate between mRNAs maternally provided or de novo transcribed from the embryonic genome in early embryos.2.To assess the functional significance of transgenerational transmission of specific histone modifications for gene activity or repression in the early embryo. We will generate transgenic mice expressing a particular histone demethylase during late stage spermiogenesis or oogenesis. Subsequently, we will study in early embryos the transcriptional and developmental consequences of absence of specific “active” or “repressive” histone modifications that are normally transmitted by paternal and/or maternal genomes at fertilization. 3.To study the contribution of specific epigenetic modifiers for lineage specification in pre-implantation embryos. We will perform genome-wide gene expression studies in pools of inner cell mass, primitive endoderm and trophectodermal cells isolated from wild-type and mutant blastocyst embryos. We will use expression of transgenic fluorescent proteins controlled by promoters of Nanog, Gata6 and Cdx to sort cells according to their cellular lineage. Distinct mutants will be studied to determine the effect of gene deficiency of epigenetic modifiers for expression and lineage specification. Expected Value: By combining Affymetrix Gene array and RNA deep-sequencing methodologies with sophisticated conditional mouse mutants and extensive bioinformatic analyses, the proposed experiments represent a systems biology approach that will generate quantitative data on transcriptional control by epigenetic master regulators during pre-implantation development. The results will lead to insights in the mechanisms of transgenerational inheritance of epigenetic information as well as in the transcriptional networks linked to the acquisition of totipotency and first lineage specification during mammalian embryogenesis. These in vivo studies will aid the elucidation of epigenetic reprogramming mechanisms implicated in the generation of induced pluripotent stem (iPS) cells in vitro.
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