Regulation of DNA Methylation Patterns by CK2-Mediated Phosphorylation of Dnmt3a

DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns

Atonal homolog 1 Is a Tumor Suppressor Gene

Colon cancer accounts for more than 10% of all cancer deaths annually. Our genetic evidence from Drosophila and previous in vitro studies of mammalian Atonal homolog 1 (Atoh1, also called Math1 or Hath1) suggest an anti-oncogenic function for the Atonal group of proneural basic helix-loop-helix transcription factors. We asked whether mouse Atoh1 and human ATOH1 act as tumor suppressor genes in vivo. Genetic knockouts in mouse and molecular analyses in the mouse and in human cancer cell lines support a tumor suppressor function for ATOH1. ATOH1 antagonizes tumor formation and growth by regulating proliferation and apoptosis, likely via activation of the Jun N-terminal kinase signaling pathway. Furthermore, colorectal cancer and Merkel cell carcinoma patients show genetic and epigenetic ATOH1 loss-of-function mutations. Our data indicate that ATOH1 may be an early target for oncogenic mutations in tissues where it instructs cellular differentiation

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

L'hétérochromatine et sa relation à la pathologie humaine

Le but de ce travail de thèse a été de mieux connaître l organisation, la composition et les fonctions de l hétérochromatine (HC) humaine. Cette partie du génome, caractérisée par son état très condensé et son inactivité transcriptionnelle, longtemps considérée comme inutile, demeure en effet mal connue. Ce travail a été essentiellement réalisé in situ, sur différents modèles d HC constitutive (télomères, régions centromériques) et facultative (vésicule sexuelle), dans des cellules normales et pathologiques. La première partie de ce travail, qui concerne l étude d une série de patients présentant une délétion de la région télomérique du chromosome 22, a conduit à la mise en évidence d un gène candidat potentiellement responsable du syndrome associé à cette délétion (syndrome 22q13). Il a aussi permis d émettre des hypothèses expliquant la tendance marquée des régions télomériques à la recombinaison et donc leur fréquente implication dans les réarrangements de ce type. La deuxième partie de ce travail a permis de démontrer que la protéine HP1, caractéristique de l HC constitutive, pouvait aussi être un constituant de l HC facultative de la vésicule sexuelle, permettant de penser que ces deux types d HC sont formés sur des bases communes. Enfin, la troisième partie, consacrée à l étude de la pathologique ICF (Immunodeficiency, Centromeric instability, Facial dysmorphy) a conduit à la mise en évidence d une certaine redondance entre les différents constituants de l HC. Cette étude a révélé la présence d une distribution altérée de la protéine HP1 à la phase G2 du cycle cellulaire, vraisemblablement liée au problème de condensation caractéristique du syndrome ICF. Enfin, cette étude a conduit à proposer l intervention des corps PML dans le processus de condensation de l HC qui précède la métaphase, fonction jusque là restée ignorée.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Codificación de cuentas. Hacia una metodología flexible y sistemática para las pequeñas y medianas empresas

Contablemente, la cuenta es el instrumento usado para el registro en forma resumida de una transacción o hecho económico. Desde la creación de la teoría de la partida doble, por Fray Luca Pacioli en el año 1445, se usan al menos dos cuentas para registrar los hechos contables. Con el avance tecnológico, particularmente con el uso contable de los sistemas de información computarizados, el código de la cuenta ha tomado gran importancia, por cuanto éste se convierte en el dato fundamental que nutre el sistema de contabilidad computarizada, y el contenido de los reportes contables va a depender de una correcta codificación. En tal sentido, esta codificación debe realizarse según criterios metodológicos que garanticen reportes financieros con la información contable acerca del período económico al que se refiere. Como resultado de la presente investigación, se presentan una serie de lineamientos a ser usados para estructurar la codificación de cuentas para las PYMES que, al ser aplicados en el diseño del catálogo de cuentas, cubrirán tanto las necesidades de información, como la correcta lectura y resultados que se arrojen a través de los diferentes reportes financieros

Hybrid humic acid/titanium dioxide nanomaterials as highly effective antimicrobial agents against gram(−) pathogens and antibiotic contaminants in wastewater

Humic acids (HAs) provide an important bio-source for redox-active materials. Their functional chemical groups are responsible for several properties, such as metal ion chelating activity, adsorption ability towards small molecules and antibacterial activity, through reactive oxygen species (ROS) generation. However, the poor selectivity and instability of HAs in solution hinder their application. A promising strategy for overcoming these disadvantages is conjugation with an inorganic phase, which leads to more stable hybrid nanomaterials with tuneable functionalities. In this study, we demonstrate that hybrid humic acid/titanium dioxide nanostructured materials that are prepared via a versatile in situ hydrothermal strategy display promising antibacterial activity against various pathogens and behave as selective sequestering agents of amoxicillin and tetracycline antibiotics from wastewater. A physicochemical investigation in which a combination of techniques were utilized, which included TEM, BET, 13C-CPMAS-NMR, EPR, DLS and SANS, shed light on the structure-property-function relationships of the nanohybrids. The proposed approach traces a technological path for the exploitation of organic biowaste in the design at the molecular scale of multifunctional nanomaterials, which is useful for addressing environmental and health problems that are related to water contamination by antibiotics and pathogens

The interplay between the lysine demethylase KDM1A and DNA methyltransferases in cancer cells is cell cycle dependent

International audienceDNA methylation and histone modifications are key epigenetic regulators of gene expression, and tight connections are known between the two. DNA methyltransferases are upregulated in several tumors and aberrant DNA methylation profiles are a cancer hallmark. On the other hand, histone demethylases are upregulated in cancer cells. Previous work on ES cells has shown that the lysine demethylase KDM1A binds to DNMT1, thereby affecting DNA methylation. In cancer cells, the occurrence of this interaction has not been explored. Here we demonstrate in several tumor cell lines an interaction between KDM1A and both DNMT1 and DNMT3B. Intriguingly and in contrast to what is observed in ES cells, KDM1A depletion in cancer cells was foundnot to trigger any reduction in the DNMT1 or DNMT3B protein level or any change in DNA methylation. In the S-phase, furthermore, KDM1A and DNMT1 were found, to colocalize within the heterochromatin. Using P-LISA, we revealed substantially increased binding of KDM1A to DNMT1 during the S-phase. Together, our findings propose a mechanistic link between KDM1A and DNA methyltransferases in cancer cells and suggest that the KDM1A/DNMT1 interaction may play a role during replication. Our work also strengthens the idea that DNMTs can exert functions unrelated to act on DNA methylation

Regulation of DNA methylation patterns by ck2-mediated phosphorylation of dnmt3a

Contains fulltext : 131557.pdf (publisher's version ) (Open Access

Savoirs de la fiction

Dès les années 2000, la fiction a cessé d’occuper le devant de la scène théorique en littérature, et pourtant, plus que jamais, sa capacité à configurer notre expérience est en débat. Expériences de pensée, phénomènes de réception de masse ou récits exemplaires, de nombreux textes littéraires modèlent non seulement notre expérience mais aussi notre capacité même à comprendre le monde dans lequel nous vivons. Cette fonction heuristique fait de la fiction un instrument de connaissance et un objet de savoir, notamment pour le droit. À travers des contributions de spécialistes issus de disciplines variées (philosophie, histoire, droit, sociologie), cet ouvrage comporte trois axes de réflexion. Tout d’abord, quels types de savoirs supposent (et développent) notre usage des fictions littéraires ou mentales ? Ensuite, les lectures juridico-historiques de la fiction seront évoquées : quel droit de la fiction ? Quelles réécritures cinématographiques ou littéraires de procès ? Quelles analogies structurelles entre texte littéraire et texte juridique ? Enfin, le rôle de la fiction dans la constitution d’imaginaires sociaux sera questionné à l’aune de ses effets sur la perception des conditions représentées et de l’efficacité critique qui en découle