Institute Of Genetique Humaine
Institute Of Genetique Humaine
Timofeev K.,UK National Institute for Medical Research |
Joly W.,UK National Institute for Medical Research |
Joly W.,Institute Of Genetique Humaine |
Hadjieconomou D.,UK National Institute for Medical Research |
Salecker I.,UK National Institute for Medical Research
Neuron | Year: 2012
A shared feature of many neural circuits is their organization into synaptic layers. However, the mechanisms that direct neurites to distinct layers remain poorly understood. We identified a central role for Netrins and their receptor Frazzled in mediating layer-specific axon targeting in the Drosophila visual system. Frazzled is expressed and cell autonomously required in R8 photoreceptors for directing their axons to the medulla-neuropil layer M3. Netrin-B is specifically localized in this layer owing to axonal release by lamina neurons L3 and capture by target neuron-associated Frazzled. Ligand expression in L3 is sufficient to rescue R8 axon-targeting defects of Netrin mutants. R8 axons target normally despite replacement of diffusible Netrin-B by membrane-tethered ligands. Finally, Netrin localization is instructive because expression in ectopic layers can retarget R8 axons. We propose that provision of localized chemoattractants by intermediate target neurons represents a highly precise strategy to direct axons to a positionally defined layer.
Le Goff C.,French Institute of Health and Medical Research |
Mahaut C.,French Institute of Health and Medical Research |
Abhyankar A.,Rockefeller University |
Le Goff W.,University Pierre and Marie Curie |
And 14 more authors.
Nature Genetics | Year: 2012
Myhre syndrome (MIM 139210) is a developmental disorder characterized by short stature, short hands and feet, facial dysmorphism, muscular hypertrophy, deafness and cognitive delay. Using exome sequencing of individuals with Myhre syndrome, we identified SMAD4 as a candidate gene that contributes to this syndrome on the basis of its pivotal role in the bone morphogenetic pathway (BMP) and transforming growth factor (TGF)-β signaling. We identified three distinct heterozygous missense SMAD4 mutations affecting the codon for Ile500 in 11 individuals with Myhre syndrome. All three mutations are located in the region of SMAD4 encoding the Mad homology 2 (MH2) domain near the site of monoubiquitination at Lys519, and we found a defect in SMAD4 ubiquitination in fibroblasts from affected individuals. We also observed decreased expression of downstream TGF-β target genes, supporting the idea of impaired TGF-β-mediated transcriptional control in individuals with Myhre syndrome.
Roesch F.,Institute Pasteur Paris |
Roesch F.,French National Center for Scientific Research |
Roesch F.,University Paris Diderot |
Meziane O.,Institute Of Genetique Humaine |
And 14 more authors.
PLoS Pathogens | Year: 2012
HIV-infected individuals may experience fever episodes. Fever is an elevation of the body temperature accompanied by inflammation. It is usually beneficial for the host through enhancement of immunological defenses. In cultures, transient non-physiological heat shock (42-45°C) and Heat Shock Proteins (HSPs) modulate HIV-1 replication, through poorly defined mechanisms. The effect of physiological hyperthermia (38-40°C) on HIV-1 infection has not been extensively investigated. Here, we show that culturing primary CD4+ T lymphocytes and cell lines at a fever-like temperature (39.5°C) increased the efficiency of HIV-1 replication by 2 to 7 fold. Hyperthermia did not facilitate viral entry nor reverse transcription, but increased Tat transactivation of the LTR viral promoter. Hyperthermia also boosted HIV-1 reactivation in a model of latently-infected cells. By imaging HIV-1 transcription, we further show that Hsp90 co-localized with actively transcribing provirus, and this phenomenon was enhanced at 39.5°C. The Hsp90 inhibitor 17-AAG abrogated the increase of HIV-1 replication in hyperthermic cells. Altogether, our results indicate that fever may directly stimulate HIV-1 replication, in a process involving Hsp90 and facilitation of Tat-mediated LTR activity. © 2012 Roesch et al.
Moniot B.,Institute Of Genetique Humaine |
Farhat A.,Institute Of Genetique Humaine |
Aritake K.,Osaka Bioscience Institute |
Declosmenil F.,Institute Of Genetique Humaine |
And 5 more authors.
Developmental Dynamics | Year: 2011
In mammals, the Prostaglandin D 2 (PGD 2) signaling pathway is involved in male gonadal development, regulating Sox9 gene expression and SOX9 protein subcellular localization through lipocalin prostaglandin D synthase (L-Pgds) activity. Nevertheless, because L-Pgds is downstream of Sox9, its expression cannot explain the initial nuclear translocation of the SOX9 protein. Here, we show that another source of PGD 2, hematopoietic-Pgds (H-Pgds) enzyme is expressed in somatic and germ cells of the embryonic gonad of both sexes, as early as embryonic day (E) 10.5, before the onset of L-Pgds expression. Inhibition of H-Pgds activity by the specific HQL-79 inhibitor leads to impaired nuclear translocation of SOX9 protein in E11.5 Sertoli cells. Furthermore, analysis of H-Pgds -/- male embryonic gonads confirms abnormal subcellular localization of SOX9 protein at the E11.5 early stage of mouse testicular differentiation suggesting a role for H-Pgds-produced PGD 2 in the initial nuclear translocation of SOX9. © 2011 Wiley-Liss, Inc.
Burkovics P.,Masaryk University |
Burkovics P.,Hungarian Academy of Sciences |
Sebesta M.,Masaryk University |
Sisakova A.,Masaryk University |
And 12 more authors.
EMBO Journal | Year: 2013
Completion of DNA replication needs to be ensured even when challenged with fork progression problems or DNA damage. PCNA and its modifications constitute a molecular switch to control distinct repair pathways. In yeast, SUMOylated PCNA (S-PCNA) recruits Srs2 to sites of replication where Srs2 can disrupt Rad51 filaments and prevent homologous recombination (HR). We report here an unexpected additional mechanism by which S-PCNA and Srs2 block the synthesis-dependent extension of a recombination intermediate, thus limiting its potentially hazardous resolution in association with a cross-over. This new Srs2 activity requires the SUMO interaction motif at its C-terminus, but neither its translocase activity nor its interaction with Rad51. Srs2 binding to S-PCNA dissociates Polδ and Polη from the repair synthesis machinery, thus revealing a novel regulatory mechanism controlling spontaneous genome rearrangements. Our results suggest that cycling cells use the Siz1-dependent SUMOylation of PCNA to limit the extension of repair synthesis during template switch or HR and attenuate reciprocal DNA strand exchanges to maintain genome stability. © 2013 European Molecular Biology Organization.
Cavalli G.,Institute Of Genetique Humaine |
Misteli T.,U.S. National Institutes of Health
Nature Structural and Molecular Biology | Year: 2013
Although genomes are defined by their sequence, the linear arrangement of nucleotides is only their most basic feature. A fundamental property of genomes is their topological organization in three-dimensional space in the intact cell nucleus. The application of imaging methods and genome-wide biochemical approaches, combined with functional data, is revealing the precise nature of genome topology and its regulatory functions in gene expression and genome maintenance. The emerging picture is one of extensive self-enforcing feedback between activity and spatial organization of the genome, suggestive of a self-organizing and self-perpetuating system that uses epigenetic dynamics to regulate genome function in response to regulatory cues and to propagate cell-fate memory. Copyright © 2013 Nature America, Inc.
Arumugam K.,University of Arkansas for Medical Sciences |
Arumugam K.,Institute Of Genetique Humaine |
Wang Y.,University of Arkansas for Medical Sciences |
Wang Y.,National Center for Toxicological Research (NCTR) |
And 3 more authors.
EMBO Journal | Year: 2010
Meiotic cell-cycle progression in progesterone-stimulated Xenopus oocytes requires that the translation of pre-existing maternal mRNAs occur in a strict temporal order. Timing of translation is regulated through elements within the mRNA 3′ untranslated region (3′ UTR), which respond to cell cycle-dependant signalling. One element that has been previously implicated in the temporal control of mRNA translation is the cytoplasmic polyadenylation element (CPE). In this study, we show that the CPE does not direct early mRNA translation. Rather, early translation is directed through specific early factors, including the Musashi-binding element (MBE) and the MBE-binding protein, Musashi. Our findings indicate that although the cyclin B5 3′ UTR contains both CPEs and an MBE, the MBE is the critical regulator of early translation. The cyclin B2 3′ UTR contains CPEs, but lacks an MBE and is translationally activated late in maturation. Finally, utilizing antisense oligonucleotides to attenuate endogenous Musashi synthesis, we show that Musashi is critical for the initiation of early class mRNA translation and for the subsequent activation of CPE-dependant mRNA translation. © 2010 European Molecular Biology Organization.
Talotta F.,CNR Institute of Neuroscience |
Mega T.,CNR Institute of Neuroscience |
Mega T.,University of Catanzaro |
Bossis G.,CNR Institute of Neuroscience |
And 6 more authors.
Oncogene | Year: 2010
Multiple tumorigenic pathways converge on the activating protein-1 (AP-1) family of dimeric transcription complexes by affecting transcription, mRNA decay, posttranslational modifications, as well as stability of its JUN and FOS components. Several mechanisms have been implicated in the phosphorylation-and ubiquitylation-dependent control of c-Jun protein stability. Although its dimer composition has a major role in the regulation of AP-1, little is known about the influence of heterodimerization partners on the half-life of c-Jun. The FOS family member Fra-1 is overexpressed in various tumors and cancer cell lines wherein it controls motility, invasiveness, cell survival and cell division. Oncogene-induced accumulation of Fra-1 results from both increased transcription and phosphorylation-dependent stabilization of the protein. In this report, we describe a novel role of Fra-1 as a posttranslational regulator of c-Jun. By using both constitutively and inducible transformed rat thyroid cell lines, we found that c-Jun is stabilized in response to RAS oncoprotein expression. This stabilization requires the activity of the extracellular signal-related kinase (ERK) pathway, along with c-Jun heterodimerization with Fra-1. In particular, heterodimerization with Fra-1 inhibits c-Jun breakdown by a mechanism dependent on the phosphorylation of the Fra-1 C-terminal domain that positively controls the stability of the protein in response to ERK signaling. Therefore, Fra-1 modulates AP-1 dimer composition by promoting the accumulation of c-Jun in response to oncogenic RAS signaling. © 2010 Macmillan Publishers Limited All rights reserved.
Pappalardo F.,National Research Council Italy |
Pappalardo F.,University of Catania |
Lefranc M.-P.,Institute Of Genetique Humaine |
Lollini P.-L.,University of Bologna |
Motta S.,University of Catania
Immunome Research | Year: 2010
Background. Biology is moving fast toward the virtuous circle of other disciplines: from data to quantitative modeling and back to data. Models are usually developed by mathematicians, physicists, and computer scientists to translate qualitative or semi-quantitative biological knowledge into a quantitative approach. To eliminate semantic confusion between biology and other disciplines, it is necessary to have a list of the most important and frequently used concepts coherently defined. Results. We propose a novel paradigm for generating new concepts for an ontology, starting from model rather than developing a database. We apply that approach to generate concepts for cell and molecule interaction starting from an agent based model. This effort provides a solid infrastructure that is useful to overcome the semantic ambiguities that arise between biologists and mathematicians, physicists, and computer scientists, when they interact in a multidisciplinary field. Conclusions. This effort represents the first attempt at linking molecule ontology with cell ontology, in IMGT-ONTOLOGY, the well established ontology in immunogenetics and immunoinformatics, and a paradigm for life science biology. With the increasing use of models in biology and medicine, the need to link different levels, from molecules to cells to tissues and organs, is increasingly important. © 2010 Pappalardo et al; licensee BioMed Central Ltd.
Contreras X.,Institute Of Genetique Humaine |
Benkirane M.,Institute Of Genetique Humaine |
Kiernan R.,Institute Of Genetique Humaine
Transcription | Year: 2013
Transcription elongation is now recognized as an important mechanism of gene regulation in eukaryotes. A large number of genes undergo an early step in transcription that is rate limiting for expression. Genome-wide studies showing that RNA polymerase II accumulates to high densities near the promoters of many genes has led to the idea that promoter-proximal pausing of transcription is a widespread, rate-limiting step in early elongation. Recent evidence suggests that much of this paused RNA polymerase II is competent for transcription elongation. Here, we discuss recent studies suggesting that RNA polymerase II that accumulates nearby the promoter of a subset of genes is undergoing premature termination of transcription.