29 research outputs found
Mapping U-238 decay chain equilibrium state in thin sections of geo-materials by digital autoradiography and microprobe analysis
A new approach is proposed in order to spatially localize and determine the equilibrium state of natural decay chains on hand-scale geological samples, thanks to a combination of three techniques: 1) Elementary chemical mapping by microprobe; 2) Alpha autoradiograph by gaseous detectors and 3) bulk alpha particle spectrometry. The quantitative nature of alpha autoradiograph and its comparison with U chemical maps allows to locate radioactive equilibrium state in four samples. This equilibrium state was confirmed by alpha spectrometry analysis.Peer reviewe
The H3K36me2 writer-reader dependency in H3K27M-DIPG
Histone H3K27M is a driving mutation in diffuse intrinsic pontine glioma (DIPG), a deadly pediatric brain tumor. H3K27M reshapes the epigenome through a global inhibition of PRC2 catalytic activity and displacement of H3K27me2/3, promoting oncogenesis of DIPG. As a consequence, a histone modification H3K36me2, antagonistic to H3K27me2/3, is aberrantly elevated. Here, we investigate the role of H3K36me2 in H3K27M-DIPG by tackling its upstream catalyzing enzymes (writers) and downstream binding factors (readers). We determine that NSD1 and NSD2 are the key writers for H3K36me2. Loss of NSD1/2 in H3K27M-DIPG impedes cellular proliferation and tumorigenesis by disrupting tumor-promoting transcriptional programs. Further, we demonstrate that LEDGF and HDGF2 are the main readers mediating the protumorigenic effects downstream of NSD1/2-H3K36me2. Treatment with a chemically modified peptide mimicking endogenous H3K36me2 dislodges LEDGF/HDGF2 from chromatin and specifically inhibits the proliferation of H3K27M-DIPG. Our results indicate a functional pathway of NSD1/2-H3K36me2-LEDGF/HDGF2 as an acquired dependency in H3K27M-DIPG
Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma
A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity
Bioinformatic analysis of post-translational modifications of the carboxy-terminal domain of RNA polymerase II
Le processus transcriptionnel par l'ARN polymérase II (Pol II) chez les eucaryotes se déroule en trois étapes : L'initiation, l'élongation et la terminaison. De nombreux facteurs de transcription, des modifications de la chromatine (épigénétique) et des éléments régulateurs distants interviennent dans ce processus. La sous-unité RPB1 de l'ARN Pol II contient un domaine carboxyle terminale (CTD) composée d'une répétition de sept acides-aminés. Au travers de différentes modifications biochimiques, ce domaine coordonne le processus transcriptionnel par le recrutement de différents facteurs. Le CTD est également impliqué dans la coordination de la transcription au niveau de l'initiation, de l'élongation et de la terminaison par le biais de modifications épigénétiques et nucléosomales, mais aussi par l'action de régulateurs distants (enhancers) et probablement de changements de conformation tridimensionnelle du génome. Mon travail de thÚse a consisté en l'étude de deux modifications biochimiques du CTD de l'ARN Pol II par traitement bioinformatique de données issues du séquençage haut-débit. J'ai pu montrer que la phosphorylation de la thréonine 4 influence l'élongation de la transcription chez l'humain. J'ai également montré que la phosphorylation de la tyrosine 1 est présente durant l'initiation, est préférentiellement localisée dans la direction anti-sens, est hyper-phosphorylée aux enhancers transcrits et tissus spécifiques et est une marque caractéristique de ces modules génomiques. Ce travail de doctorat a constitué une contribution à la compréhension du processus transcriptionnel chez l'humain par l'utilisation de méthodes bioinformatiques innovantes.The biggest subunit of eukaryotic RNA polymerase II contains a carboxy-terminal domain (CTD) that consists in a repetition of seven amino-acids ranging from 26 in yeast to 52 in mammals. Specific biochemical modifications of CTD residues have been linked to specific stages of the transcriptional process. The CTD acts as a recruitment platform for processing factors that are involved in initiation, promoter proximal pausing, early and productive elongation (alternative splicing), 3' processing, termination and epigenetics.During my PhD, I used bioinformatics and high-throughput sequencing data to study two novel biochemical modifications of the CTD in human. I showed, in collaboration with biologists and bioinformaticians, that threonine 4 phosphorylation is important for proper elongation and probably termination of transcription. I showed also that tyrosine 1 phosphorylation is present during early transcription, antisense transcription (at divergent promoters) and is hyperphosphorylated at transcribed and tissue specific enhancers.Overall my doctorate has contributed to the understanding of the transcriptional process in human through the use of innovative bioinformatic methods
Long-Term Evolution of Uranium Mobility within Sulfated Mill Tailings in Arid Regions: A Reactive Transport Study
International audienceManagement of mill tailings is an important part of mining operations that aims at preventing environmental dispersion of contaminants of concern. To this end, geochemical models and reactive transport modeling provide a quantitative assessment of the mobility of the main contaminants. In arid regions with limited rainfall and intense evaporation, solutes transport may significantly differ from the usual gravity-driven vertical flow. In the uranium tailings of the Cominak mine (Niger), these evaporative processes resulted in the crystallization of gypsum, and to a lesser extent jarosite, and in the formation of surface levels of sulfated gypcrete, locally enriched in uranium. We present a fully coupled reactive transport modeling approach using HYTEC, encompassing evaporation, to quantitatively reproduce the complex sequence of observed coupled hydrogeochemical processes. The sulfated gypcrete formation, porosity evolution and solid uranium content were successfully reproduced at the surface and paleosurfaces of the tailing deposit. Simulations confirm that high solubility uranyl-sulfate phase may form at the atmospheric boundary where evaporation takes place, which would then be transformed into uranyl-phosphate phases after being watered or buried under fresh tailings. As these phases usually exhibit a lower solubility, this transition is beneficial for mine operators and tailings management
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Active and Repressed Chromatin Domains Exhibit Distinct Nucleosome Segregation During DNA Replication
Chromatin domains and their associated structures must be faithfully inherited through cellular division to maintain cellular identity. Yet, accessing the localized strategies preserving chromatin domain inheritance, specifically the transfer of parental, pre-existing nucleosomes with their associated post-translational modifications (PTMs) during DNA replication is challenging in living cells. We devised an inducible, proximity-dependent labeling system to irreversibly mark replication-dependent H3.1 and H3.2 histone-containing nucleosomes at single desired loci in mouse embryonic stem cells such that their fate after DNA replication could be followed. Strikingly, repressed chromatin domains are preserved through the local re-deposition of parental nucleosomes. In contrast, nucleosomes decorating active chromatin domains do not exhibit such preservation. Notably, altering cell fate leads to an adjustment in the positional inheritance of parental nucleosomes that reflects the corresponding changes in chromatin structure. These findings point to important mechanisms that contribute to parental nucleosome segregation to preserve cellular identity
Solubility properties of synthetic and natural meta-torbernite
International audienceMeta-torbernite, Cu(UO2)2(PO4)2â
8H2O, is one of the most common secondary minerals resulting from the alteration of pitchblende. The determination of the thermodynamic data associated to this phase appears to be a crucial step toward the understanding the origin of uranium deposits or to forecast the fate and transport of uranium in natural media. A parallel approach based on the study of both synthetic and natural samples of meta-torbernite (H3O)0.4Cu0.8(UO2)2(PO4)2â
7.6H2O was set up to evaluate its solubility constant. The two solids were first thoroughly characterized and compared by means of XRD, SEM, X-EDS analyses, Raman spectroscopy and BET measurements. The solubility constant was then determined in both under- and supersaturated conditions: the obtained value appeared close to logKs,0°" role="presentation">Ks,0°Ks,0°(298 K) = â52.9 ± 0.1 whatever the type of experiment and the sample considered. The joint determination of Gibbs free energy (ÎRG°(298 K) = 300 ± 2 kJ molâ1) then allowed the calculation of ÎRH°(298 K) = 40 ± 3 kJ molâ1 and ÎRS°(298 K) = â879 ± 7 J molâ1 Kâ1. From these values, the thermodynamic data associated with the formation of meta-torbernite (H3O)0.4Cu0.8(UO2)2(PO4)2â
7.6H2O were also evaluated and found to be consistent with those previously obtained by calorimetry, showing the reliability of the method developed in this work. Finally, the obtained data were implemented in a calculation code to determine the conditions of meta-torbernite formation in environmental conditions typical of a former mining site
Solubility properties of synthetic and natural meta-torbernite
International audienceMeta-torbernite, Cu(UO2)2(PO4)2â
8H2O, is one of the most common secondary minerals resulting from the alteration of pitchblende. The determination of the thermodynamic data associated to this phase appears to be a crucial step toward the understanding the origin of uranium deposits or to forecast the fate and transport of uranium in natural media. A parallel approach based on the study of both synthetic and natural samples of meta-torbernite (H3O)0.4Cu0.8(UO2)2(PO4)2â
7.6H2O was set up to evaluate its solubility constant. The two solids were first thoroughly characterized and compared by means of XRD, SEM, X-EDS analyses, Raman spectroscopy and BET measurements. The solubility constant was then determined in both under- and supersaturated conditions: the obtained value appeared close to logKs,0°" role="presentation">Ks,0°Ks,0°(298 K) = â52.9 ± 0.1 whatever the type of experiment and the sample considered. The joint determination of Gibbs free energy (ÎRG°(298 K) = 300 ± 2 kJ molâ1) then allowed the calculation of ÎRH°(298 K) = 40 ± 3 kJ molâ1 and ÎRS°(298 K) = â879 ± 7 J molâ1 Kâ1. From these values, the thermodynamic data associated with the formation of meta-torbernite (H3O)0.4Cu0.8(UO2)2(PO4)2â
7.6H2O were also evaluated and found to be consistent with those previously obtained by calorimetry, showing the reliability of the method developed in this work. Finally, the obtained data were implemented in a calculation code to determine the conditions of meta-torbernite formation in environmental conditions typical of a former mining site
Procédé d'immobilisation de l'uranium dans les eaux naturelles par précipitation d'un phosphate d'uranyle
La présente invention concerne un procédé pour séparer l'uranium d'une solution aqueuse contenant ledit uranium, ce procédé comprenant une étape consistant à mettre en contact ladite solution aqueuse contenant ledit uranium avec une hydroxyapatite dopée au cuivre moyennant quoi de la métatorbernite précipitée à la surface de l'hydroxyapatite dopée au cuivre et une solution épurée en uranium sont obtenues. La présente invention concerne également un procédé de préparation de ladite hydroxyapatite dopée au cuivre et ladite hydroxyapatite dopée au cuivre ainsi préparée