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    ABSTRACT: Lineage specification in the preimplantation mouse embryo is a regulative process. Thus, it has been difficult to ascertain whether segregation of the inner-cell-mass (ICM) into precursors of the pluripotent epiblast (EPI) and the differentiating primitive endoderm (PE) is random or influenced by developmental history. Here, our results lead to a unifying model for cell fate specification in which the time of internalization and the relative contribution of ICM cells generated by two waves of asymmetric divisions influence cell fate. We show that cells generated in the second wave express higher levels of Fgfr2 than those generated in the first, leading to ICM cells with varying Fgfr2 expression. To test whether such heterogeneity is enough to bias cell fate, we upregulate Fgfr2 and show it directs cells towards PE. Our results suggest that the strength of this bias is influenced by the number of cells generated in the first wave and, mostly likely, by the level of Fgf signalling in the ICM. Differences in the developmental potential of eight-cell- and 16-cell-stage outside blastomeres placed in the inside of chimaeric embryos further support this conclusion. These results unite previous findings demonstrating the importance of developmental history and Fgf signalling in determining cell fate.
    Open Biology 11/2013; 3(11):130104. DOI:10.1098/rsob.130104
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    ABSTRACT: RNA interference defends against viral infection in plant and animal cells. The nematode Caenorhabditis elegans and its natural pathogen, the positive-strand RNA virus Orsay, have recently emerged as a new animal model of host-virus interaction. Using a genome-wide association study in C. elegans wild populations and quantitative trait locus mapping, we identify a 159 base-pair deletion in the conserved drh-1 gene (encoding a RIG-I-like helicase) as a major determinant of viral sensitivity. We show that DRH-1 is required for the initiation of an antiviral RNAi pathway and the generation of virus-derived siRNAs (viRNAs). In mammals, RIG-I-domain containing proteins trigger an interferon-based innate immunity pathway in response to RNA virus infection. Our work in C. elegans demonstrates that the RIG-I domain has an ancient role in viral recognition. We propose that RIG-I acts as modular viral recognition factor that couples viral recognition to different effector pathways including RNAi and interferon responses. DOI:http://dx.doi.org/10.7554/eLife.00994.001.
    eLife Sciences 10/2013; 2:e00994. DOI:10.7554/eLife.00994
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    ABSTRACT: Epigenetic reprogramming of parental genomes following fertilization is important to ensure compatibility for totipotency and development thereafter. New studies by Jiang et al. and Potok et al. now demonstrate how the parental DNA methylomes are reset in zebrafish and reveal striking differences from events in mammals.
    Cell 05/2013; 153(4):737-9. DOI:10.1016/j.cell.2013.04.044
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    Genome biology 04/2013; 14(4):114. DOI:10.1186/gb-2013-14-4-114
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    ABSTRACT: DNA methylation is dynamically remodelled during the mammalian life cycle through distinct phases of reprogramming and de novo methylation. These events enable the acquisition of cellular potential followed by the maintenance of lineage-restricted cell identity, respectively, a process that defines the life cycle through successive generations. DNA methylation contributes to the epigenetic regulation of many key developmental processes including genomic imprinting, X-inactivation, genome stability and gene regulation. Emerging sequencing technologies have led to recent insights into the dynamic distribution of DNA methylation during development and the role of this epigenetic mark within distinct genomic contexts, such as at promoters, exons or imprinted control regions. Additionally, there is a better understanding of the mechanistic basis of DNA demethylation during epigenetic reprogramming in primordial germ cells and during pre-implantation development. Here, we discuss our current understanding of the developmental roles and dynamics of this key epigenetic system.
    Philosophical Transactions of The Royal Society B Biological Sciences 01/2013; 368(1609):20110328. DOI:10.1098/rstb.2011.0328
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    ABSTRACT: Germ cell development is a step-wise process that ensures the progression of the life cycle due to their unique ability to transmit their genome from one generation to the next. In the mouse, the precursors of germ cells, the Primordial Germ Cells (PGCs), arise at the onset of gastrulation. Here we discuss how PGCs acquire their fate in the epiblast and outline their development until their arrival into the gonads. Male germ cell tumors (GCTs) have a similar gene expression pattern to that of fetal germ cells and to pluripotent cells, suggesting that GCT originate from an alteration of gonocyte normal development. We evaluate coincidences and differences in germ cell development in mouse and humans and on this basis, we speculate future research perspectives.
    The International journal of developmental biology 01/2013; 57(2-3-4):123-132. DOI:10.1387/ijdb.130132fb
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    ABSTRACT: Mouse postimplantation epiblast cultured in activin and basic fibroblast growth factor gives rise to continuously growing epiblast stem cells (EpiSCs) that share key properties with postimplantation epiblast, such as DNA methylation and an inactive X-chromosome. EpiSCs also show a distinct gene expression profile compared to embryonic stem cells (ESCs) derived from preimplantation blastocysts, and do not contribute efficiently to chimeras. EpiSCs can, however, revert to pluripotent ESC-like cells upon exposure to leukemia inhibitory factor-Stat3 signalling on feeder cells. Here we describe a protocol for the establishment of EpiSCs and their reversion to ESCs.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 1074:15-29. DOI:10.1007/978-1-62703-628-3_2
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    ABSTRACT: Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genome-wide DNA demethylation to reset the epigenome for totipotency. Here, we demonstrate that erasure of CpG methylation (5mC) in PGCs occurs via conversion to 5-hydroxymethylcytosine (5hmC), driven by high levels of TET1 and TET2. Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5-E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, we identify rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.
    Science 12/2012; 339(6118). DOI:10.1126/science.1229277
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    ABSTRACT: Within tissues, cells sense differences in fitness levels and this can lead to fitter cells eliminating less fit, albeit viable, cells via competitive cell interactions. The involvement of several cancer-related genes in this phenomenon has drawn attention to a potential connection between competitive cell interactions and cancer. Indeed, initial studies found that tumor-promoting genes can turn cells into 'supercompetitors', able to kill normal cells around them. However, more recently it has been observed that cells harboring certain cancer-promoting mutations can be eliminated by surrounding normal cells, suggesting that competitive cell interactions could also have a tumor-suppressive role. These findings suggest a new view whereby tumor and host cells engage in a bidirectional tug of war, the outcome of which may have a profound impact on disease progression.
    Trends in cell biology 12/2012; 23. DOI:10.1016/j.tcb.2012.11.002
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    ABSTRACT: During cell competition fitter cells take over the tissue at the expense of viable, but less fit, cells, which are eliminated by induction of apoptosis or senescence. This probably acts as a quality-control mechanism to eliminate suboptimal cells and safeguard organ function. Several experimental conditions have been shown to trigger cell competition, including differential levels in ribosomal activity or in signalling pathway activation between cells, although it is unclear how those differences are sensed and translated into fitness levels. Many of the pathways implicated in cell competition have been previously linked with cancer, and this has led to the hypothesis that cell competition could play a role in tumour formation. Cell competition could be co-opted by cancer cells to kill surrounding normal cells and boost their own tissue colonization. However, in some cases, cell competition could have a tumour suppressor role, as cells harbouring mutations in a subset of tumour suppressor genes are killed by wild-type cells. Originally described in developing epithelia, competitive interactions have also been observed in some stem cell niches, where they play a role in regulating stem cell selection, maintenance and tissue repopulation. Thus competitive interactions could be relevant to the maintenance of tissue fitness and have a protective role against aging.
    Essays in Biochemistry 08/2012; 53(1):69-82. DOI:10.1042/bse0530069
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