PR-Set7–dependent lysine methylation ensures genome replication and stability through S phase

PR-Set7/SET8 is a histone H4–lysine 20 methyltransferase required for normal cell proliferation. However, the exact functions of this enzyme remain to be determined. In this study, we show that human PR-Set7 functions during S phase to regulate cellular proliferation. PR-Set7 associates with replication foci and maintains the bulk of H4-K20 mono- and trimethylation. Consistent with a function in chromosome dynamics during S phase, inhibition of PR-Set7 methyltransferase activity by small hairpin RNA causes a replicative stress characterized by alterations in replication fork velocity and origin firing. This stress is accompanied by massive induction of DNA strand breaks followed by a robust DNA damage response. The DNA damage response includes the activation of ataxia telangiectasia mutated and ataxia telangiectasia related kinase–mediated pathways, which, in turn, leads to p53-mediated growth arrest to avoid aberrant chromosome behavior after improper DNA replication. Collectively, these data indicate that PR-Set7–dependent lysine methylation during S phase is an essential posttranslational mechanism that ensures genome replication and stability

Three-dimensional chromatin interactions remain stable upon CAG/CTG repeat expansion

Expanded CAG/CTG repeats underlie 13 neurological disorders, including myotonic dystrophy type 1 (DM1) and Huntington's disease (HD). Upon expansion, disease loci acquire heterochromatic characteristics, which may provoke changes to chromatin conformation and thereby affect both gene expression and repeat instability. Here, we tested this hypothesis by performing 4C sequencing at the DMPK and HTT loci from DM1 and HD-derived cells. We find that allele sizes ranging from 15 to 1700 repeats displayed similar chromatin interaction profiles. This was true for both loci and for alleles with different DNA methylation levels and CTCF binding. Moreover, the ectopic insertion of an expanded CAG repeat tract did not change the conformation of the surrounding chromatin. We conclude that CAG/CTG repeat expansions are not enough to alter chromatin conformation in cis. Therefore, it is unlikely that changes in chromatin interactions drive repeat instability or changes in gene expression in these disorders

Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. Theseinteractions takeplace in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.Institut National du Cancer (INCa, France, in part); European Commission (EC) Seventh Framework Programme (FP7) Translational Cancer Research (TRANSCAN) Framework; Fondation ARC pour la Recherche sur le Cancer (France) (to Z.H.); Fonds National de la Recherche, Luxembourg [10100060 to A.S.]; IARC Fellowship (Marie Curie actions – People – COFUND to N.F.J., in part); PoSTDoctoral Fellowship of the Basque Government; Swiss National Science Foundation (SNSF) (to L.V., V.Y., R.M.). Funding for open access charge: IARC regular budge

Gains énergétiques globaux par installation de pompes à chaleur dans un procédé agro-alimentaire

Thèse confidentielle jusqu'au 31 octobre 2013 Co-encadrement de la thèse : Assaad ZoughaibThe improvement of energy efficiency in the industry is essential in achieving the objective of mitigation of greenhouse gases. In the agro food process industry, lukewarm effluents are rejected to drain. Recovering heat from these effluents by using preheating exchangers and heat pumps (HP) allows providing heat at higher temperature levels (like cleaning solutions and hot sanitary water) and replacing boilers. These needs may concern batch and semi-batch processes. Storage tanks are therefore used together with heat pumps. The optimization of heat pumps and storage tanks sizes is a multi-objective method. This method is based on a thermodynamic criterion (calculating the exergy destruction in the system) and an economic criterion (calculating the payback period, the cost of investment and the operating cost, and integrating the environmental impact). The dynamic exergy analysis shows that using two separated storage tanks (variable volume and uniform temperature tanks) is better than one tank (constant volume stratified storage tank). On the other hand, a multi-criteria method is used to design heat pumps in order to maximize its performances. It allows designing optimal mixtures of refrigerants. These choices are validated experimentally with a heat pump prototype. Finally, the economic and environmental gains obtained with the heat pump compared to a fuel boiler are quantified for all heat demands.L'amélioration de l'efficacité énergétique dans l'industrie est un des leviers importants pour la limitation des émissions de gaz à effet de serre. Dans l'industrie agro-alimentaire, des effluents tièdes sont rejetés aux égouts. La valorisation de l'énergie contenue dans ces effluents à l'aide d'échangeurs préchauffeurs et de pompes à chaleur (PAC) permet d'assurer des besoins de chaleur à des niveaux de température plus élevés (comme les solutions de lavage des outils et l'eau chaude sanitaire) et de remplacer les chaudières. Ces besoins concernent souvent des procédés batch ou semi-batch; pour cela, des réservoirs de stockage sont utilisés avec les pompes à chaleur. L'optimisation des tailles des pompes à chaleur et des réservoirs de stockage est une méthode multi-objectifs; elle est basée sur un critère thermodynamique (calculant la destruction d'éxergie dans le système) et un critère économique (calculant le temps de retour sur investissement, le coût d'investissement et le coût opérationnel et intégrant l'impact environnemental). La méthodologie de l'analyse exergétique en dynamique a montré que l'utilisation de deux réservoirs de stockage (à température constante et à volume variable séparés) est plus avantageuse (économiquement et exergétiquement) que l'usage d'un seul réservoir stratifié à volume constant. D'autre part, une méthodologie multicritères est proposée et utilisée pour concevoir les pompes à chaleur, et choisir le mélange de fluides frigorigènes. Ces choix sont validés expérimentalement avec un prototype de pompes à chaleur pour les différents niveaux de température. Finalement, les gains économiques et environnementaux apportés par ces pompes à chaleur comparativement à une chaudière à fioul sont quantifiés pour les différents besoins

Interplay between different epigenetic modifications and mechanisms

Cellular functions including transcription regulation, DNA repair, and DNA replication need to be tightly regulated. DNA sequence can contribute to the regulation of these mechanisms. This is exemplified by the consensus sequences that allow the binding of specific transcription factors, thus regulating transcription rates. Another layer of regulation resides in modifications that do not affect the DNA sequence itself but still results in the modification of chromatin structure and properties, thus affecting the readout of the underlying DNA sequence. These modifications are dubbed as "epigenetic modifications" and include, among others, histone modifications, DNA methylation, and small RNAs. While these events can independently regulate cellular mechanisms, recent studies indicate that joint activities of different epigenetic modifications could result in a common outcome. In this chapter, I will attempt to recapitulate the best known examples of collaborative activities between epigenetic modifications. I will emphasize mostly on the effect of crosstalks between epigenetic modifications on transcription regulation, simply because it is the most exposed and studied aspect of epigenetic interactions. I will also summarize the effect of epigenetic interactions on DNA damage response and DNA repair. The involvement of epigenetic crosstalks in cancer formation, progression, and treatment will be emphasized throughout the manuscript. Due to space restrictions, additional aspects involving histone replacements [Park, Y. J., and Luger, K. (2008). Histone chaperones in nucleosome eviction and histone exchange. Curr. Opin. Struct. Biol.18, 282-289.], histone variants [Boulard, M., Bouvet, P., Kundu, T. K., and Dimitrov, S. (2007). Histone variant nucleosomes: Structure, function and implication in disease. Subcell. Biochem. 41, 71-89; Talbert, P. B., and Henikoff, S. (2010). Histone variants-Ancient wrap artists of the epigenome. Nat. Rev. Mol. Cell Biol.11, 264-275.], and histone modification readers [de la Cruz, X., Lois, S., Sanchez-Molina, S., and Martinez-Balbas, M. A. (2005). Do protein motifs read the histone code? Bioessays27, 164-175; Grewal, S. I., and Jia, S. (2007). Heterochromatin revisited. Nat. Rev. Genet.8, 35-46.] will not be addressed in depth in this chapter, and the reader is referred to the reviews cited here

TRRAP une protéine polyvalente (implication de TRRAP co-facteur des HAT, dans la réparation de l'ADN et dans d'autres processus cellulaires utilisant la chromatine)

TRRAP protein is a common component of several histone acetyltransferase (HAT) complexes. TRRAP and histone acetylation have been mainly studied in the context of gene transcription, however they have been recently implicated in other chromatin based processes. The main goal of our study was to investigate the role of TRRAP and histone acetylation in DNA repair. We demonstrated that TRRAP is implicated in two major types of double strand breaks repair, homologous recombination and non homologous end joining. The role of TRRAP in repair is either HAT-dependent leading to chromatin relaxation thus allowing the access of DNA repair proteins to the sites of breaks, or HAT-independent as a member of the MRN complex. In the second part of the thesis, we have identified two novel functions of TRRAP: First, we demonstrated that TRRAP is implicated in the Wnt signalling pathway, through ubiquitination of b-catenin on the chromatin. Second, TRRAP was shown to regulate the selfrenewal of hematopoietic stem cells through its transcription cofactor activity. Together, our results highlight the mutifunctional role of TRRAP and histone acetylation in the regulation and coordination of chromatin based processesLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Gains énergétiques globaux par installation de pompes à chaleur dans un procédé agro-alimentaire

L'amélioration de l'efficacité énergétique dans l'industrie est un des leviers importants pour la limitation des émissions de gaz à effet de serre. Dans l'industrie agro-alimentaire, des effluents tièdes sont rejetés aux égouts. La valorisation de l'énergie contenue dans ces effluents à l'aide d'échangeurs préchauffeurs et de pompes à chaleur (PAC) permet d'assurer des besoins de chaleur à des niveaux de température plus élevés (comme les solutions de lavage des outils et l'eau chaude sanitaire) et de remplacer les chaudières. Ces besoins concernent souvent des procédés batch ou semi-batch; pour cela, des réservoirs de stockage sont utilisés avec les pompes à chaleur. L'optimisation des tailles des pompes à chaleur et des réservoirs de stockage est une méthode multi-objectifs; elle est basée sur un critère thermodynamique (calculant la destruction d'éxergie dans le système) et un critère économique (calculant le temps de retour sur investissement, le coût d'investissement et le coût opérationnel et intégrant l'impact environnemental). La méthodologie de l'analyse exergétique en dynamique a montré que l'utilisation de deux réservoirs de stockage (à température constante et à volume variable séparés) est plus avantageuse (économiquement et exergétiquement) que l'usage d'un seul réservoir stratifié à volume constant. D'autre part, une méthodologie multicritères est proposée et utilisée pour concevoir les pompes à chaleur, et choisir le mélange de fluides frigorigènes. Ces choix sont validés expérimentalement avec un prototype de pompes à chaleur pour les différents niveaux de température. Finalement, les gains économiques et environnementaux apportés par ces pompes à chaleur comparativement à une chaudière à fioul sont quantifiés pour les différents besoins.PARIS-MINES ParisTech (751062310) / SudocSudocFranceF

Thermo economic method to design optimal scheme for water / water heat pump systems with storage tanks

International audienc

Multi-objective optimization of a multi water-to-water heat pump system using evolutionary algorithm

International audienceThis paper deals with the energy recovery in the dairy industry. Thermodynamic, economic and environmental optimization of three water-to-water heat pumps has been studied in order to replace totally or partially a fuel boiler used to produce heat at different temperature levels in a cheese factory. These heat pumps have their evaporators connected to one effluents source and two of them are equipped by storage tanks at the condenser side. Multi-objective optimization permits optimal repartition of mass flow rates of effluents and optimal choice of electrical power of the compressors and volumes of storage tanks. The thermodynamic objective is based on the exergy destruction in the whole system. The economic objective is based on the investment cost and the operating cost obtained with the heat pump system. The environmental impact objective has been defined and expressed in cost terms by considering a CO 2 taxation (carbon tax) on the GHG emissions. This objective has been integrated with the economic objective. Multi-objective genetic algorithms are used for Pareto approach optimization