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

Rétention de l'uranium et de l'europium sur la pyrite

Congrès le 7 et 8 Septembre 2006. Communications Orales

Interaction de l'uranium (VI) avec la pyrite (FeS2).

Communications Orale

Uranium (VI) interaction with pyrite (FeS2): chemical and spectroscopic studies.

International audienceThe mechanism of uranium(VI) interaction with pyrite was studied by solution chemistry and X-ray Photoelectron Spectroscopy (XPS). Natural pyrite was characterized by X-Ray Diffraction (XRD) and Scanning Electron Microscopy (SEM). After equilibration in 10(-2) moI L-1 NaNO3, pyrite was reacted with uranium(VI) by the batch method in an anoxic glove box (P-O2 < 1 ppm) at ambient temperature. The reaction products of uranium, iron and sulphur were characterized (oxidation state, chemical environment) by XPS. Quantitative analysis revealed that only a few atomic percent of uranium is retained at the pyrite surface. The U4f core level binding energies are consistent with the coexistence of an uranium(VI) species and of uranium in a reduced form. No sulphur oxidation products were observed by XPS, but spectral decomposition of the Fe 2p lines revealed the presence of iron(III) oxide or (oxy)hydroxide. These results seem to point to a redox reaction between uraniurn(VI) and pyrite

Interaction de l'uranium (VI) et de la pyrite (FeS2)

Conférence les 10 et 11 mars 2005. Communication par affiche

Uptake of uranium and trace elements in pyrite (FeS₂) suspensions

International audiencePyrite dissolution and interaction with Fe(II), Co(II), Eu(III) and U(VI) have been studied under anoxic conditions by solution chemistry and spectroscopic techniques. Aqueous data show a maximal cation uptake above pH 5.5. Iron (II) uptake can explain the non-stoichiometric [S]aq/[Fe]aq ratios often observed during dissolution experiments. Protonation data corrected for pyrite dissolution resulted in a proton site density of 9&nbsp;±&nbsp;3&nbsp;sites&nbsp;nm−2. Concentration isotherms for Eu(III) and U(VI) sorption on pyrite indicate two different behaviours which can be related to the contrasted redox properties of these elements. For Eu(III), sorption can be explained by the existence of a unique site with a saturation concentration of 1.25&nbsp;×&nbsp;10−6&nbsp;mol&nbsp;g−1. In the U(VI) case, sorption seems to occur on two different sites with a total saturation concentration of 4.5&nbsp;×&nbsp;10−8&nbsp;mol&nbsp;g−1. At lower concentration, uranium reduction occurs, limiting the concentration of dissolved uranium to the solubility of UO2(s).Scanning electron microscopy and micro-Raman spectrometry of U(VI)-sorbed pyrite indicate a heterogeneous distribution of U at the pyrite surface and a close association with oxidized S. X-ray photoelectron spectroscopy confirms the partial reduction of U and the formation of a hyperstoichiometric UO2+x(s). Our results are consistent with a chemistry of the pyrite surface governed not by Fe(II)-bound hydroxyl groups, but by S groups which can either sorb cations and protons, or sorb and reduce redox-sensitive elements such as U(VI)