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The developmental role of LET-418/Mi-2 in C. elegans

English title The developmental role of LET-418/Mi-2 in C. elegans
Applicant Müller Fritz
Number 125577
Funding scheme Project funding (Div. I-III)
Research institution Département de Biologie Faculté des Sciences Université de Fribourg
Institution of higher education University of Fribourg - FR
Main discipline Embryology, Developmental Biology
Start/End 01.05.2009 - 30.09.2014
Approved amount 415'000.00
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Keywords (15)

LET-418/Mi-2; NuRD; C. elegans; Epigenetics; Cell fate determination; Stem cell; Germline; Pluripotency; Germline-soma differentiation; chromatin remodelling; histone modification; Mi-2; LET-418; CHD-3; development

Lay Summary (English)

Lead
Lay summary
The epigenetic profile of cells changes dynamically during development of multicellular organisms and is critical for cell fate, differentiation and maintaining pluripotency. The evolutionarily conserved chromatin remodelling protein Mi-2 plays an important role in distinct aspects of germline and early embryonic development, particularly during developmental transitions. Although Mi-2 was first identified as an integral component of the human NuRD complex, it becomes increasingly clear that Mi-2 has also NuRD independent functions. Moreover, Mi-2 orthologues were shown to be involved in important developmental processes, such as homeostasis and lineage choice of haematopoietic stem cells in mammals, the transition of pluripotent cells from pre- to post-implantation of mouse embryos and embryonic patterning and germline development in D. melanogaster and germline-soma distinction in C. elegans. Specific aimsMi-2 functions, particularly outside of NuRD, are not well understood. Therefore we use C. elegans as a model system to investigate the cellular and developmental functions of the eukaryotic Mi-2 protein family. The genome of Caenorhabditis elegans encodes two Mi-2 orthologs, LET-418/Mi-2 and CHD-3/Mi-2. The aim of this project is to analyze the specific roles of LET-418/Mi-2 in embryogenesis and in germline development. Particularly, we are interested in knowing whether let-418/Mi-2 plays a role in stem cell division in the distal region of the gonad. Genetic screens will allow uncovering new players in the regulation of germline chromatin, and microarray expression profiling of let-418/Mi-2 animals should provide crucial information about the functions of let-418/Mi-2 in regulating germline-specific genes during embryogenesis. Finally, we propose to perform genome-wide RNAi screens to uncover additional, yet unknown functions of let-418/Mi-2 and its paralogue chd-3/Mi-2.Expected value of the projectSince Mi-2 is conserved among eukaryotes, characterizing the role of C. elegans LET-418/Mi-2 in the remodelling of germline and somatic chromatin should contribute to the general understanding of epigenetic programming. For instance, the precise resetting of epigenetic modifications during gametogenesis is crucial to sustain fertilization and further development in all organisms. Hence, the implication for human health and reproduction may be profound.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
- LET-418/Mi2 and SPR-5/LSD1 cooperatively prevent somatic reprogramming of C.elegans germline stem cells
Stefanie Kaeser-Pebernard (2014), - LET-418/Mi2 and SPR-5/LSD1 cooperatively prevent somatic reprogramming of C.elegans germline stem cells, in Stem cell reports, 2(4), 547-559.
Specific NuRD components are required for fin regeneration in zebrafish
Catherine Pfefferli (2014), Specific NuRD components are required for fin regeneration in zebrafish, in BMC Biology, 12:30, 12:30.
The mitochondrial genome of Parascaris univalens - implications for a “forgotten” parasite
Abdul Jabbar (2014), The mitochondrial genome of Parascaris univalens - implications for a “forgotten” parasite, in Parasites & Vectors, 7, 428.
The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation
Véronique De Vaux (2013), The Caenorhabditis elegans LET-418/Mi2 plays a conserved role in lifespan regulation, in Aging Cell, 12(5), 1012-1020.
LIN-39 and the EGFR/RAS/MAPK pathway regulate C. elegans vulval morphogenesis via the VAB-23 zinc finger protein
Mark W. Pellegrino (2011), LIN-39 and the EGFR/RAS/MAPK pathway regulate C. elegans vulval morphogenesis via the VAB-23 zinc finger protein, in Development, 141, 639-649.
Different Mi-2 Complexes for Various Developmental Functions in Caenorhabditis elegans
M. Passannante (2010), Different Mi-2 Complexes for Various Developmental Functions in Caenorhabditis elegans, in Plos One , issue 10, e13681.
The C. elegans Hox gene ceh-13 regulates cell migration and fusion in a non-colinear way. Implications for the early evolution of Hox clusters
Borbála Tihanyi (2010), The C. elegans Hox gene ceh-13 regulates cell migration and fusion in a non-colinear way. Implications for the early evolution of Hox clusters, in BMC Developmental Biolopgy, 10, 78.
The C. elegans sex determination protein MOG-3 functions in meiosis and binds to the CSL co-repressor CIR-1
Prasad Kasturi (2010), The C. elegans sex determination protein MOG-3 functions in meiosis and binds to the CSL co-repressor CIR-1, in Developmental Biology, 344(2), 593-602.

Associated projects

Number Title Start Funding scheme
128665 Confocal microscopy-based dissection of the subcellular architecture in fly, worm and plant cells 01.02.2010 R'EQUIP
109938 Molecular and genetic analysis of the NuRD complex in the nematode C. elegans 01.10.2005 Project funding (Div. I-III)
129019 Composition and genome-wide function of NuRD and MEC chromatin remodeling complexes during C.elegans development 01.02.2010 Marie Heim-Voegtlin grants

Abstract

BackgroundThe epigenetic profile of cells changes dynamically during development and is critical for cell fate, differentiation and maintaining pluripotency. Analyses in various model organisms suggest that the evolutionarily conserved chromatin remodelling protein Mi-2 plays an important role in distinct aspects of germline and early embryonic development, particularly during developmental transitions. Although Mi-2 was first identified as an integral component of the canonical NuRD complex, it becomes now increasingly clear that Mi-2 has also NuRD independent functions. Mi-2 orthologues were shown to be involved in important developmental processes, such as homeostasis and lineage choice of haematopoietic stem cells in mouse, the transition of pluripotent cells from pre- to post-implantation of mouse embryos, embryonic patterning and germline development in D. melanogaster and germline-soma distinction in C. elegans. Moreover, the A. thaliana Mi-2 orthologue Pickle is required for repression of seed-associated genes in the transition from inert seeds to growing seedlings and for suppression of embryonic development in meristem cells to allow the transition to post-embryonic development. While much progress has been made in understanding chromatin-mediated control of gene activity in general, much less is still known about the specific developmental functions of Mi-2 and the molecular mechanisms that are associated with it.Working hypothesisDuring developmental transitions in C. elegans, important epigenetic reprogramming is taking place. Based on previous results we postulate that LET-418/Mi-2 is taking part of this reprogramming. For instance, we think that LET-418/Mi-2 is playing a role in shutting down the germline expression profile already during oogenesis to get the genome ready for somatic development. Another epigenetic reprogramming is taking place when the germline starts to develop. Our experiments are designed to better understand the role of let-418/Mi-2 in these processes and to identify additional players.Specific aimsTo better understand the developmental functions of the Mi-2 protein family, we will use C. elegans as a genetic model system to investigate the cellular and developmental functions of LET-418/Mi-2. First, we will analyze the role of LET-418/Mi-2 for germline development, particularly during the proliferation phase and during oogenesis and oocyte maturation. Particularly, we are interested in knowing whether let-418/Mi-2 has a role in stem cell division in the distal region of the gonad, and whether it is involved in the chromatin transitions during oogenesis and in Z2/Z3 during embryogenesis. Genetic screens will allow uncovering new players in the regulation of germline chromatin, and microarray expression profiling of let-418/Mi-2 animals should provide crucial information about the functions of let-418/Mi-2 in regulating germline-specific genes. We will also perform a phenotypic analysis of the germline of let-418/Mi-2 males and investigate the antagonistic functions of let-418 and mes-4. Finally, we propose to perform genome-wide RNAi screens to identify additional developmental functions of let-418/Mi-2 and its paralogue chd-3/Mi-2.Expected value of the proposed projectSince Mi-2 is conserved among eukaryotes, characterizing the role of C. elegans LET-418/Mi-2 in the remodelling of germline and somatic chromatin should contribute to the general understanding of epigenetic programming. For instance, the precise resetting of epigenetic modifications during gametogenesis is crucial to sustain fertilization and further development in all organisms. Hence, the implication for human health and reproduction are profound.
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