Analyse de la régulation de l'homéostasie des télomères et de la chromatine dans le maintien de l'intégrité génomique chez la levure Saccharomyces cerevisiae

Toute l'information génétique octroyant l'existence à une cellule est encodée par les milliards de paires de bases d'ADN retrouvées principalement à l'intérieur du noyau. Toutefois, pour des raisons d'espace et d'accessibilité, tout cet ADN est soumis à de nombreuses étapes de compaction en plus d'être fractionné dans le but de former ultimement les chromosomes. Malgré que l'extrême compaction de l'ADN permette la protection des acides nucléiques contre la dégradation, certaines structures demeurent vulnérables et nécessitent une protection toute particulière. C'est le cas de séquences se retrouvant à l'extrémité des chromosomes, les télomères. Les télomères sont constitués de répétitions en tandem d'ADN non codant associées avec de nombreuses protéines spécialisées permettant une protection efficace contre la perte d'informations génétiques dû à la dégradation enzymatique ou à l'érosion naturelle. Ces structures télomériques sont normalement maintenues par une machinerie spécialisée, la télomérase, qui composée d'une sous unité ARN et de partenaires protéiques permet l'ajout de séquences télomériques spécifiquement aux extrémités. Cette enzyme essentielle est régulée par de nombreuses protéines et parmi celles-ci, de nombreuses observations font état du rôle essentiel joué par deux protéines kinases, les protéines Tel1p et Mec1p. Ces kinases occupent une double fonction; elles sont importantes pour la régulation de la taille des télomères, mais sont également au coeur de la réponse cellulaire face aux dommages à l'ADN. Étant donné la nature des télomères, soit des extrémités d'ADN libres, ceux-ci sont identiques en de nombreux points aux cassures double brins d'ADN expliquant probablement la double implication de ces protéines. Durant mes études, je me suis particulièrement intéressé à la double fonction jouée par les kinases Tel1p et Mec1p au niveau des télomères et du processus de réponse aux dommages à l'ADN. Dans un premier temps, avec l'aide d'un collègue j'ai pu démontrer l'étendue des fonctions télomériques et de réponses aux dommages à l'ADN jouées par Tel1p via l'isolation et la caractérisation d'un allèle de séparation de fonctions. Dans un deuxième temps, en poursuivant mes analyses génétiques sur la kinase Tel1p, j'ai pu déterminer que cette protéine possédait des fonctions indépendantes à celles octroyées par son domaine kinase, observation allant à l'encontre de l'idée générale que Tel1p sans fonction kinase opérationnelle simulait un allèle nul. Dans la même ligne de pensée, mes études ont permis d'identifier un nouveau mécanisme de régulation de la télomérase essentiel joué par les kinases Mec1p et Tel1p. En parallèle, je me suis intéressé aux mécanismes cellulaires permettant une régulation de l'enroulement global de l'ADN permettant son accessibilité à toutes les machineries cellulaires de transcription, de réparation et de réplication de l'ADN. Mes travaux ont permis d'identifier qu'une modification des histones, protéines critiques dans le processus de compaction de l'ADN, était extrêmement importante dans le processus de réponse aux dommages à l'ADN. En effet la triméthylation de l'histone H3 sur sa lysine 4 permet à la cellule de pouvoir efficacement réparer les dommages via la réparation de bout non-homologue et permettait de stabiliser les fourches de réplications soumises à un stress cellulaire. Globalement mes résultats m'ont permis de mieux comprendre deux moyens distincts utilisés par les cellules pour maintenir l'intégrité de leur génome : les rôles joués par les kinases Tel1p et Mec1p aux télomères et dans la réparation des dommages à l'ADN, ainsi que l'implication de la modification d'histone H3K4me3 dans le processus de réponse aux dommages à l'ADN

Statistics of gamma-ray point sources below the Fermi detection limit

An analytic relation between the statistics of photons in pixels and the number counts of multi-photon point sources is used to constrain the distribution of gamma-ray point sources below the Fermi detection limit at energies above 1 GeV and at latitudes below and above 30 degrees. The derived source-count distribution is consistent with the distribution found by the Fermi collaboration based on the first Fermi point source catalogue. In particular, we find that the contribution of resolved and unresolved active galactic nuclei (AGN) to the total gamma-ray flux is below 20% - 25%. In the best fit model, the AGN-like point source fraction is 17% +- 2%. Using the fact that the Galactic emission varies across the sky while the extra-galactic diffuse emission is isotropic, we put a lower limit of 51% on Galactic diffuse emission and an upper limit of 32% on the contribution from extra-galactic weak sources, such as star-forming galaxies. Possible systematic uncertainties are discussed.Comment: 26 pages, 10 figures, 1 table; v2: clarifications and references added, v3: more detailed presentation of the metho

Age-Related Decline in Reproductive Sensitivity to Inhibition by Short Photoperiod in Peromyscus Leucopus

Seasonal environments favor the timing, of reproduction to match seasons when Successful reproduction is most likely. Most species of temperate zone mammals suppress reproduction in winter using changes in day length as a cue. In many species, individuals vary genetically in how strongly they respond to these seasonal cues. Individuals also may modify their response to day length depending upon other factors, including their age. Age-specific changes might occur because young, peripubertal rodents are more strongly affected by harsh conditions than adults, and therefore might be more sensitive to inhibitory photoperiods. We tested the hypothesis that genetic variation in responses to photoperiod persists as individuals age. Young males from a captive population of white-footed mice (Peromyscus leucopus) that is genetically variable for reproductive inhibition by short day length (SD) were tested for photoperiod responses. Mice were placed in SD within 3 days after birth, tested at age 70 days, allowed to mature for at least 18 weeks at long day length, and then tested again as adults aged \u3e= 34 weeks. Young males were more likely to be strongly reproductively Suppressed by SD than adults, indicating that age-specific changes in reproductive strategy occur in this Population. However, males that were reproductively photoresponsive when young also were more likely to be reproductively photoresponsive as adults. Thus, genetic tendency for reproductive sensitivity to photoperiod is a trait retained from puberty to adulthood, but attenuates with age

Extended Lyman-Alpha Emission around Star-forming Galaxies

Lyman-alpha (Lya) photons that escape the interstellar medium of star-forming galaxies may be resonantly scattered by neutral hydrogen atoms in the circumgalactic and intergalactic media, thereby increasing the angular extent of the galaxy's Lya emission. We present predictions of this extended, low surface brightness Lya emission based on radiative transfer modeling in a cosmological reionization simulation. The extended emission can be detected from stacked narrowband images of Lya emitters (LAEs) or of Lyman break galaxies (LBGs). Its average surface brightness profile has a central cusp, then flattens to an approximate plateau beginning at an inner characteristic scale below ~0.2 Mpc (comoving), then steepens again beyond an outer characteristic scale of ~1 Mpc. The inner scale marks the transition from scattered light of the central source to emission from clustered sources, while the outer scale marks the spatial extent of scattered emission from these clustered sources. Both scales tend to increase with halo mass, UV luminosity, and observed Lya luminosity. The extended emission predicted by our simulation is already within reach of deep narrowband photometry using large ground-based telescopes. Such observations would test radiative transfer models of emission from LAEs and LBGs, and they would open a new window on the circumgalactic environment of high-redshift star-forming galaxies.Comment: 14 pages, 10 figures, accepted for publication in ApJ, revised according to the referee's comments, more discussions and test

Mean-flux Regulated PCA Continuum Fitting of SDSS Lyman-alpha Forest Spectra

Continuum fitting is an important aspect of Lyman-alpha forest science, since errors in the estimated optical depths scale with the fractional continuum error. However, traditional methods of estimating continua in noisy and moderate-resolution spectra (S/N < 10 pixel^-1 and R ~ 2000, respectively, such as SDSS) using power-law extrapolation or the mean spectrum, achieve no better than ~ 10-15% RMS accuracy. To improve on this, we introduce mean-flux regulated/principal component analysis (MF-PCA) continuum fitting. In this technique, PCA fitting is carried out redwards of the quasar Lyman-alpha line in order to provide a prediction for the shape of the Lyman-alpha forest continuum. The slope and amplitude of this continuum prediction is then corrected using external constraints for the Lyman-alpha forest mean-flux. From tests on mock spectra, we find that MF-PCA reduces the errors to 8% RMS in S/N ~ 2 spectra, and 5. The residual Fourier power in the continuum is decreased by a factor of a few in comparison with dividing by the mean continuum, enabling Lyman-alpha flux power spectrum measurements to be extended to ~2x larger scales. Using this new technique, we make available continuum fits for 12,069 z>2.3 Lyman-alpha forest spectra from SDSS DR7 for use by the community. This technique is also applicable to future releases of the ongoing BOSS survey, which is obtaining spectra for ~ 150,000 Lyman-alpha forest spectra at low signal-to-noise (S/N ~ 2).Comment: 14 pages; 11 figures; submitted to AJ. Continua publicly available via anonymous FTP or Data Conservancy repositor

He II Ly{\beta} Gunn-Peterson Absorption: New HST Observations, and Theoretical Expectations

Observations of He II Ly{\alpha} Gunn-Peterson troughs have proved to be a valuable probe of the epoch of helium reionization at z~3. Since this optical depth can become unmeasurably large even for modest He II fractions, various alternate techniques have been proposed to push to higher redshift, and among the more promising is looking at higher order Lyman-series troughs. We here report four new observations of the He II Ly{\beta} trough, including new data on the only sightline with a prior Ly{\beta} observation. However, the effective optical depth ratio {\tau}_eff,{\beta}/{\tau}_eff,{\alpha} is not simply predicted by (f_{\beta} {\lambda}_{\beta})/(f_{\alpha} {\lambda}_{\alpha})=0.16, and we analyze cosmological simulations to find that the correct ratio for helium at z~3 is ~0.35. In one case we infer {\tau}_eff,{\alpha} > 8.8, strong evidence that helium was not fully reionized at z=3.2--3.5, in agreement with previous measurements suggesting a later completion of reionization.Comment: ApJ accepted. 25 pages, 3 figures, 4 table

Pressure Support vs. Thermal Broadening in the Lyman-alpha Forest II: Effects of the Equation of State on Transverse Structure

We examine the impact of gas pressure on the transverse coherence of high-redshift (2 <= z <= 4) Lyman-alpha forest absorption along neighboring lines of sight that probe the gas Jeans scale (projected separation Delta r <= 500 kpc/h comoving; angular separation Delta theta <= 30"). We compare predictions from two smoothed particle hydrodynamics (SPH) simulations that have different photoionization heating rates and thus different temperature-density relations in the intergalactic medium (IGM). We also compare spectra computed from the gas distributions to those computed from the pressureless dark matter. The coherence along neighboring sightlines is markedly higher for the hotter, higher pressure simulation, and lower for the dark matter spectra. We quantify this coherence using the flux cross-correlation function and the conditional distribution of flux decrements as a function of transverse and line-of-sight (velocity) separation. Sightlines separated by Delta theta <= 15" are ideal for probing this transverse coherence. Higher pressure decreases the redshift-space anisotropy of the flux correlation function, while higher thermal broadening increases the anisotropy. In contrast to the longitudinal (line-of-sight) structure of the Lya forest, the transverse structure on these scales is dominated by pressure effects rather than thermal broadening. With the rapid recent growth in the number of known close quasar pairs, paired line-of-sight observations offer a promising new route to probe the IGM temperature-density relation and test the unexpectedly high temperatures that have been inferred from single sightline analyses.Comment: 11 figures, submitted to MNRA