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Understanding molecular mechanisms underlying chromatin reprogramming during male germ cell development

English title Understanding molecular mechanisms underlying chromatin reprogramming during male germ cell development
Applicant Peters Antoine Hendrik Felix Marie
Number 172873
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 01.04.2017 - 31.03.2021
Approved amount 1'008'000.00
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All Disciplines (4)

Discipline
Embryology, Developmental Biology
Biochemistry
Genetics
Molecular Biology

Keywords (5)

chromatin; nucleosome; epigenetics; spermatogenesis; fertility

Lay Summary (German)

Lead
Schwerpunkt der vorgeschlagenen Forschungsarbeit ist die Untersuchung des DNA-Verpackungsmaterials in Spermien und dessen potenzielle Rolle bei der Übertragung epigenetischer Informationen vom Vater auf die Nachkommen.
Lay summary

Die Befruchtung stellt im Lebenszyklus von Säugetieren den Moment dar, in dem die genetische Information zweier Individuen zusammengebracht wird, um ein neues Individuum hervorzubringen. Eine wesentliche Frage in der Biologie ist, (a) ob, (b) in welchem Umfang und (c) in welcher Form reife Keimzellen über die DNA-Sequenz hinaus Informationen in sich tragen, die für die Entwicklung der Nachkommen wichtig sind.
Wir konzentrieren unsere Forschungstätigkeit bei diesem Projekt auf die Untersuchung des Aufbaus von Chromatin, dem Verbund von Histonproteinen und DNA (Nukleosomen), in sich entwickelnden männlichen Keimzellen. Unser Ziel ist es, a) die Mechanismen zu analysieren, die zur Definition der verschiedenen nukleosomalen Chromatinkonfigurationen in reifen Spermien führen, und b) herauszufinden, ob und welche Chromatinkonfigurationen Aufschluss auf die Spezifizierung der Embryonalentwicklung geben. Um die Funktion verschiedener Histonproteine bei der Entwicklung männlicher Keimzellen zu verstehen, kombinieren wir Maustransgenese, Molekulargenetik sowie epigenomische und biochemische Methoden miteinander. Zur Identifikation von Faktoren, die während der Kernkondensation haploider Keimzellen bei der Verdrängung bzw. der Retention von Nukleosomen eine Rolle spielen, werden wir proteomische Analysen von isoliertem Chromatin aus sich entwickelnden Keimzellen durchführen. Unser Ziel ist letztlich, die Lokalisation von Nukleosomen in einzelnen Spermien zu bestimmen und deren Bedeutung bei der Übertragung epigentischer Informationen zwischen zwei Generationen zu beurteilen.
Wir gehen davon aus, dass durch diese Forschungsarbeit unser Verständnis der regulatorischen Rolle von Chromatin bei der Entwicklung männlicher Gameten und der Übertragung epigenetischer Informationen auf die nachfolgende Generation vertieft wird.

Direct link to Lay Summary Last update: 20.11.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Kmt2b conveys monovalent and bivalent H3K4me3 in mouse spermatogonial stem cells at germline and embryonic promoters
Tomizawa Shin-ichi, Kobayashi Yuki, Shirakawa Takayuki, Watanabe Kumiko, Mizoguchi Keita, Hoshi Ikue, Nakajima Kuniko, Nakabayashi Jun, Singh Sukhdeep, Dahl Andreas, Alexopoulou Dimitra, Seki Masahide, Suzuki Yutaka, Royo Hélène, Peters Antoine H. F. M., Anastassiadis Konstantinos, Stewart A. Francis, Ohbo Kazuyuki (2018), Kmt2b conveys monovalent and bivalent H3K4me3 in mouse spermatogonial stem cells at germline and embryonic promoters, in Development, 145(23), dev169102-dev169102.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited seminar at RIKEN – 9th Epigenetics seminar series Individual talk Chromatin based control of germ cell and early embryonic development 13.12.2019 Yokohama, Japan Peters Antoine Hendrik Felix Marie;
Invited seminar at NATIONAL INSTITUTE FOR BASIC BIOLOGY, Okazaki, Japan Individual talk Chromatin based control of germ cell and early embryonic development 09.12.2019 Okazaki, Japan Peters Antoine Hendrik Felix Marie;
Invited seminar at Department of Stem Cell Biology and Medicine, Kyushu University Individual talk Epigenetic control of mammalian germ line and early embryonic development 02.12.2019 Fukuoka, Japan , Japan Peters Antoine Hendrik Felix Marie;
Invited seminar at Izmir Biomedicine & Genome Center, Izmir, Turkey Individual talk Epigenetic control of mammalian germ line and early embryonic development 25.10.2019 Izmir, Turkey Peters Antoine Hendrik Felix Marie;
Epigenetic inheritance Symposium 2019 Talk given at a conference Aberrant paternal transmission of nucleosomes impairs transcription in and development of early mouse embryos 27.08.2019 Zurich, Switzerland Peters Antoine Hendrik Felix Marie;
Invited seminar at Institute Curie, Paris Individual talk Chromatin based control of germ cell and early embryonic development in mice 15.02.2019 Paris, France Peters Antoine Hendrik Felix Marie;
Invited seminar at Institut Cochin, Paris Individual talk Chromatin based control of germ cell and early embryonic development in mice 14.02.2019 Paris, France Peters Antoine Hendrik Felix Marie;
Invited seminar at MRC Institute of Genetics & Molecular Medicine Individual talk Chromatin based control of germ cell and early embryonic development in mice 27.11.2018 Edinburgh, Great Britain and Northern Ireland Peters Antoine Hendrik Felix Marie;
Invited seminar at MRC Centre for Reproductive Health, University of Edinburgh Individual talk Chromatin based control of germ cell and early embryonic development in mice 26.11.2018 Edinburgh, Great Britain and Northern Ireland Peters Antoine Hendrik Felix Marie;


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

Abstract

In the life cycle of mammalian organisms, fertilization represents the moment at which genetic information of two individuals is united to give rise to a new individual. A major question in biology is whether and/or to what extent mature gametes carry information beyond the DNA sequence that is important for the development of offspring. Over recent years, numerous studies involving mammalian systems provided some evidence for inter- and/or transgenerational inheritance of phenotypic traits in response to external environmental cues, such as altered nutrition, chemical pollutants, and endocrine disruptors. Alterations in DNA methylation, composition of small RNAs and/or chromatin states have been implicated in the inheritance of such traits, yet, clear mechanistic insights are rather limiting. To elucidate molecular mechanisms involved in such acquired forms of epigenetic inheritance, we aim to dissect (a) the fundamental mechanisms involved in defining chromatin states in mature gametes in unchallenged conditions, and (b) whether such states are instructive in specifying embryonic development. In this proposal, we focus on the development of male germ cells. Following an almost eight week lasting developmental process millions of highly differentiated haploid spermatozoa are day-to-day generated from, originally, a few spermatogonial stem cells. Upon leaving the spermatogonial stem cell pool, differentiating spermatogonia undergo first multiple rounds of replication and thenceforth enter into meiosis to undergo meiotic recombination and haploidisation. During the following spermiogenesis phase, haploid spermatids dramatically remodel their chromatin structure and undertake a major cellular morphogenesis process resulting in the generation of highly compacted and motile sperm.We and others have previously shown that nucleosomes, the basic building units of chromatin, remain present at specific sequences in mature sperm of mouse and men. Ongoing experiments indicate that H3 proteins in nucleosomes “change their identity” by the exchange of canonical replication dependent H3.1 and H3.2 proteins by a testis specific isoform called H3t as well as by the H3.3 variant histone. H3t is conserved among mammals and harbors a few amino acid substitutions relative to H3.1. H3t deficient animals display major defects in the proliferative differentiating spermatogoia and reduced H3.3 levels cause spermatogenic arrest at different stages, pending on residual levels. In this proposal, we combine mouse transgenesis, molecular genetic, epigenomic, and biochemical approaches to understand the function of the H3t and H3.3 histone variants, and to test the role of specific amino acid residues and their post-translational modifications in male germ cell development. We further focus on the mechanisms underlying global transcriptional silencing occurring at the end of spermatogenesis. We propose to perform proteomic analyses of chromatin isolated from developing spermatids to identify novel factors involved in nuclear condensation and nucleosome eviction versus retention. Finally, we aim to determine the localization of nucleosomes in individual spermatozoa and assess their relevance for intergenerational transmission of epigenetic information.We believe that this research will enhance our understanding of the regulatory role of chromatin in male gamete generation and transmission of epigenetic information to the next generation.
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