Éditeur(s) : HAL CCSD
Résumé : Understanding of the mechanisms driving diversification of species is a significant way to improve the management of ecosystems, predict the impacts of climate change and understand the actual and past biodiversity level. The aim of this thesis is to understand and comprehend genetic mechanisms behind the diversification of species in the presence of gene flow. This thesis is focused on the biological model Symphonia globulifera, which presents two ecotypes: the S.globulifera, specialist of seasonally flooded lowlands and S.sp1, specialist of terra firme. These two ecotypes show low genetic differentiation, despite the presence of two apparent phenotypes. A first part of this thesis was to test the presence of local adaptation of this using reciprocal transplant experiment gardens, allowing the understanding of the ecotypes distributions in their natural habitats. Then, this local adaptation in the presence of gene flow, directed me to the regulation of gene methylation in order to see the role this brand of epigenetics can have in the divergence of the ecotypes. In a third part of the thesis, new generation sequencing of the transcriptome ecotypes in reciprocal gardens transplantations allowed me to show the evidence of gene regulation to differentiate the ecotypes. This work thesis is based on phenotype records data, AFLP genotyping and high-throughput sequencing of the transcriptome, in order to show the important value of gene regulation in the divergence of the locally adapted ecotypes, and a weak role of DNA methylation in the establishment of local adaptation.
Connaitre et appréhender les mécanismes de la diversification des espèces est important pour la gestion des écosystèmes, la prévision des impacts des changements climatiques et la compréhension de la biodiversité actuelle et passée. Le but de cette thèse est de comprendre et de déceler les mécanismes génétiques à l’origine de la diversification des espèces en présence de flux de gènes. Cette thèse se focalise sur le modèle biologique Symphonia globulifera, qui compte deux écotypes : le S.globulifera spécialiste de la terra firme et le S.sp1, spécialiste des bas-fonds. Ces deux écotypes montrent une faible différenciation génétique, malgré la présence de deux phénotypes différents.Une première étape a été de mettre en évidence la présence d’une adaptation locale au sein de cette espèce, par le biais d’une expérimentation de jardins de transplantation réciproques, permettant d’expliquer la répartition des écotypes dans leur habitat naturel. Ensuite, dans le but d’identifier les mécanismes sous-jacent à cette adaptation locale, j’ai testé l’hypothèse que la méthylation des gènes pourrait être une marque de l’épigénétique contribuant à la divergence des écotypes, par l’utilisation d’enzyme sensibles à la méthylation dans un protocole de génotypage AFLP. Enfin, un séquençage haut-débit du transcriptome des écotypes en jardins de transplantation réciproques m’a permis de mettre en évidence une expression différentielle des gènes entre les écotypes, qui pourrait expliquer les différences phénotypiques observées entre les écotypes malgré une faible différentiation génétique. Ces travaux de thèse s’appuie, ainsi, sur des données de traits phénotypiques, de génotypage AFLP et de séquençage à haut débit du transcriptome pour montrer la valeur importante de la régulation des gènes dans la divergence des écotypes adaptés localement, et un faible rôle de la méthylation de l’ADN dans l’établissement cette adaptation locale.
https://tel.archives-ouvertes.fr/tel-01405400

NNT : 2015YANE0005
tel-01405400
https://tel.archives-ouvertes.fr/tel-01405400
https://tel.archives-ouvertes.fr/tel-01405400/document
https://tel.archives-ouvertes.fr/tel-01405400/file/these_-_tinaut.pdf

Éditeur(s) : HAL CCSD MDPI
Résumé : International audience
In mammals, the effects of estrogen are mainly mediated by two different estrogen receptors, ERα and ERβ. These proteins are members of the nuclear receptor family, characterized by distinct structural and functional domains, and participate in the regulation of different biological processes, including cell growth, survival and differentiation. The two estrogen receptor (ER) subtypes are generated from two distinct genes and have partially distinct expression patterns. Their activities are modulated differently by a range of natural and synthetic ligands. Some of these ligands show agonistic or antagonistic effects depending on ER subtype and are described as selective ER modulators (SERMs). Accordingly, a few phytochemicals, called phytoestrogens, which are synthesized from plants and vegetables, show low estrogenic activity or anti-estrogenic activity with potentially anti-proliferative effects that offer nutraceutical or pharmacological advantages. These compounds may be used as hormonal substitutes or as complements in breast cancer treatments. In this review, we discuss and summarize the in vitro and in vivo effects of certain phytoestrogens and their potential roles in the interaction with estrogen receptors.
ISSN: 1422-0067

hal-01560283
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01560283
PUBMED : 28657580
DOI : 10.3390/ijms18071381

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
A hallmark of living systems is the management and the storage of information through genetic and epigenetic mechanisms. Although the notion of epigenetics was originally given to any regulation beyond DNA sequence, it has often been restricted to chromatin modifications, supposed to behave as cis-markers, specifying the sets of genes to be expressed or repressed. This definition does not take into account the initial view of epigenetics, based on nonlinear interaction networks whose "attractors" can remain stable without need for any chromatin mark. In addition, most chromatin modifications are the steady state resultants of highly dynamic modification and de-modification activities and, as such, seem poorly appropriate to work as long-term memory keepers. Instead, the basic support of epigenetic memory could remain the attractors, to which chromatin modifications belong as do many other components. The influence of chromatin modifications in memory is highly questionable when envisioned as static structural marks, but can be recovered under the dynamic circuitry perspective, thanks to their self-templating properties. Beside their standard repressive or permissive functions, chromatin modifications can also influence transcription in multiple ways such as: (1) by randomizing or inversely stabilizing gene expression, (2) by mediating cooperativity between pioneer and secondary transcription factors, and (3) in the hysteresis and the ultrasensitivity of gene expression switches, allowing the cells to take unambiguous transcriptional decisions.
ISSN: 1420-682X

hal-01063617
https://hal.archives-ouvertes.fr/hal-01063617
DOI : 10.1007/s00018-012-0923-7
PUBMED : 22331281

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
EXOSC10 is a catalytic subunit of the exosome that processes biologically active transcripts, degrades aberrant mRNAs and targets certain long non-coding RNAs (lncRNAs). The yeast orthologue Rrp6 is required for efficient growth and gametogenesis, and becomes unstable during meiosis. However, nothing is known about the localization, stability and function of EXOSC10 in the rodent male germline. We detect the protein in nucleoli and the cytoplasm of mitotic and meiotic germ cells, and find that it transiently associates with the XY body, a structure targeted by meiotic sex chromosome inactivation (MSCI). Finally, EXOSC10 becomes unstable at later stages of gamete development. To determine Exosc10's meiotic function, we inactivated the gene specifically in male germ cells using cre recombinase controlled by Stra8 or Ddx4/Vasa promoters. Mutant mice have small testes, show impaired germ cell differentiation and are subfertile. Our results demonstrate that EXOSC10 is post-translationally regulated in germ cells, associate the protein with epigenetic chromosome silencing, and reveal its essential role in germ cell growth and development.
ISSN: 2045-2322

hal-01647082
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01647082
DOI : 10.1038/s41598-017-14643-y
PUBMED : 29118343

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
Epigenetics, as a DNA signature that affects gene expression and enables rapid reaction of an organism to environmental changes, is likely involved in the process of biological invasions. DNA methylation is an epigenetic mechanism common to plants and animals for regulating gene expression. In this study we show, for the first time in any marine species, significant reduction of global methylation levels during the expansive phase of a pygmy mussel (Xenostrobus securis) recent invasion in Europe (twoyear old), while in older introductions such epigenetic signature of invasion was progressively reduced. Decreased methylation was interpreted as a rapid way of increasing phenotypic plasticity that would help invasive populations to thrive. This epigenetic signature of early invasion was stronger than the expected environmental signature of environmental stress in younger populations sampled from ports, otherwise detected in a much older population (>90 year old) of the also invasive tubewormFicopomatus enigmaticus established in similar locations. Higher epigenetic than genetic diversity found in X. securis was confirmed from F. enigmaticus samples. As reported for introduced plants and vertebrates, epigenetic variation could compensate for relatively lower genetic variation caused by founder effects. These phenomena were compared with epigenetic mechanisms involved in metastasis, as parallel processes of community (biological invasion) and organism (cancer) invasions.
ISSN: 2045-2322

hal-01488962
https://hal-univ-perp.archives-ouvertes.fr/hal-01488962
https://hal-univ-perp.archives-ouvertes.fr/hal-01488962/document
https://hal-univ-perp.archives-ouvertes.fr/hal-01488962/file/Epigenetic.pdf
DOI : 10.1038/srep42193

Éditeur(s) : HAL CCSD Oxford University Press
Résumé : International audience
It was recently reported that the sizes of many mRNAs change when budding yeast cells exit mitosis and enter the meiotic differentiation pathway. These differences were attributed to length variations of their untranslated regions. The function of UTRs in protein translation is well established. However, the mechanism controlling the expression of distinct transcript isoforms during mitotic growth and meiotic development is unknown. In this study, we order developmentally regulated transcript isoforms according to their expression at specific stages during meiosis and gametogenesis, as compared to vegetative growth and starvation. We employ regulatory motif prediction, in vivo protein-DNA binding assays, genetic analyses and monitoring of epigenetic amino acid modification patterns to identify a novel role for Rpd3 and Ume6, two components of a histone deacetylase complex already known to repress early meiosis-specific genes in dividing cells, in mitotic repression of meiosis-specific transcript isoforms. Our findings classify developmental stage-specific early, middle and late meiotic transcript isoforms, and they point to a novel HDAC-dependent control mechanism for flexible transcript architecture during cell growth and differentiation. Since Rpd3 is highly conserved and ubiquitously expressed in many tissues, our results are likely relevant for development and disease in higher eukaryotes.
ISSN: 0305-1048

Droits : http://creativecommons.org/licenses/by/
hal-01122128
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122128
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122128/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01122128/file/The%20conserved%20histone%20deacetylase.pdf
DOI : 10.1093/nar/gku1185

Éditeur(s) : HAL CCSD Springer Verlag
Résumé : International audience
Chromatin modification enzymes are important regulators of gene expression and some are evolutionarily conserved from yeast to human. Saccharomyces cerevisiae is a major model organism for genome-wide studies that aim at the identification of target genes under the control of conserved epigenetic regulators. Ume6 interacts with the upstream repressor site 1 (URS1) and represses transcription by recruiting both the conserved histone deacetylase Rpd3 (through the co-repressor Sin3) and the chromatin-remodeling factor Isw2. Cells lacking Ume6 are defective in growth, stress response, and meiotic development. RNA profiling studies and in vivo protein-DNA binding assays identified mRNAs or transcript isoforms that are directly repressed by Ume6 in mitosis. However, a comprehensive understanding of the transcriptional alterations, which underlie the complex ume6Δ mutant phenotype during fermentation, respiration, or sporulation, is lacking. We report the protein-coding transcriptome of a diploid MAT a/α wild-type and ume6/ume6 mutant strains cultured in rich media with glucose or acetate as a carbon source, or sporulation-inducing medium. We distinguished direct from indirect effects on mRNA levels by combining GeneChip data with URS1 motif predictions and published high-throughput in vivo Ume6-DNA binding data. To gain insight into the molecular interactions between successive waves of Ume6-dependent meiotic genes, we integrated expression data with information on protein networks. Our work identifies novel Ume6 repressed genes during growth and development and reveals a strong effect of the carbon source on the derepression pattern of transcripts in growing and developmentally arrested ume6/ume6 mutant cells. Since yeast is a useful model organism for chromatin-mediated effects on gene expression, our results provide a rich source for further genetic and molecular biological work on the regulation of cell growth and cell differentiation in eukaryotes.
ISSN: 1617-4615

hal-01151619
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01151619
DOI : 10.1007/s00438-015-1051-5
PUBMED : 25957495

Éditeur(s) : HAL CCSD
Résumé : International audience
The epigenetic mark 5-hydroxymethylcytosine (5hmC) is a cytosine modification that is abundant in the central nervous system of mammals and which results from 5-methylcytosine oxidation by TET enzymes. Such a mark is suggested to play key roles in the regulation of chromatin structure and gene expression. However, its precise functions still remain poorly understood and information about its distribution in non-mammalian species is still lacking. Here, the distribution of 5hmC was investigated in the brain of adult zebrafish, African claw frog, and mouse in a comparative manner. We show that zebrafish neurons are endowed with high levels of 5hmC, whereas quiescent or proliferative neural progenitors show low to undetectable levels of the modified cytosine. In the brain of larval and juvenile Xenopus, 5hmC is also detected in neurons, while ventricular proliferative cells do not display this epigenetic mark. Similarly, 5hmC is enriched in neurons compared to neural progenitors of the ventricular zone in the mouse developing cortex. Interestingly, 5hmC colocalized with the methylated DNA binding protein MeCP2 and with the active chromatin histone modification H3K4me2 in mouse neurons. Taken together, our results show an evolutionarily conserved cerebral distribution of 5hmC between fish and tetrapods and reinforce the idea that 5hmC fulfills major functions in the control of chromatin activity in vertebrate neurons. J. Comp. Neurol. 525:478-497, 2017. © 2016 Wiley Periodicals, Inc.
Journal of Comparative Neurology

hal-01439354
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01439354
DOI : 10.1002/cne.24077
PUBMED : 27414756

Éditeur(s) : HAL CCSD Cold Spring Harbor Laboratory Press
Résumé : “Human and Environmental Genomics” platform (Rennes) for Illumina sequencing / Proteomics Core Facility of the Cambridge Institute (Cancer Research UK)
International audience
Epigenetic mechanisms are believed to play key roles in the establishment of cell-specific transcription programs. Accordingly, the modified bases 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been observed in DNA of genomic regulatory regions such as enhancers, and oxidation of 5mC into 5hmC by Ten-eleven translocation (TET) proteins correlates with enhancer activation. However, the functional relationship between cytosine modifications and the chromatin architecture of enhancers remains elusive. To gain insights into their function, 5mC and 5hmC levels were perturbed by inhibiting DNA methyltransferases and TETs during differentiation of mouse embryonal carcinoma cells into neural progenitors, and chromatin characteristics of enhancers bound by the pioneer transcription factors FOXA1, MEIS1, and PBX1 were interrogated. In a large fraction of the tested enhancers, inhibition of DNA methylation was associated with a significant increase in monomethylation of H3K4, a characteristic mark of enhancer priming. In addition, at some specific enhancers, 5mC oxidation by TETs facilitated chromatin opening, a process that may stabilize MEIS1 binding to these genomic regions.
ISSN: 1088-9051

Droits : http://creativecommons.org/licenses/by-nc/
hal-01533248
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248/document
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01533248/file/Genome%20Res.-2017-Mah%C3%A9-947-58.pdf
DOI : 10.1101/gr.211466.116

Éditeur(s) : HAL CCSD Elsevier
Résumé : International audience
Seventy percent of breast tumors express the estrogen receptor (ER), which is generally considered to predict a better outcome relative to ER-negative tumors, as they often respond to antiestrogen therapies. During cancer progression, mammary tumors can escape from estrogen control, resulting in the acquisition of invasive properties and resistance to treatment. ER expression is a dynamic phenomenon and is finely regulated at numerous levels, including the gene, mRNA, and protein levels. As a consequence, many molecular mechanisms have been implicated in modulating ER activity and estrogen signaling in mammary cancer. In fact, one-third of ER-positive breast cancer cells do not respond to first-line endocrine therapies, and a large subset of relapsing tumors retain ER expression. Increased knowledge of these mechanisms has led to the development of better prognostic methods and targeted therapies for patients; however, additional research is still needed to improve patient survival. In this chapter, we focus on the signaling pathways leading to changes in or loss of ER activity in breast cancer progression.
ISSN: 0083-6729

hal-00874313
https://hal.archives-ouvertes.fr/hal-00874313
DOI : 10.1016/B978-0-12-416673-8.00004-6
PUBMED : 23810005

Éditeur(s) : HAL CCSD Nature Publishing Group
Résumé : International audience
DNA cytosine methylation is a widely conserved epigenetic mark in eukaryotes that appears to have critical roles in the regulation of genome structure and transcription. Genome-wide methylation maps have so far only been established from the supergroups Archaeplastida and Unikont. Here we report the first whole-genome methylome from a stramenopile, the marine model diatom Phaeodactylum tricornutum. Around 6% of the genome is intermittently methylated in a mosaic pattern. We find extensive methylation in transposable elements. We also detect methylation in over 320 genes. Extensive gene methylation correlates strongly with transcriptional silencing and differential expression under specific conditions. By contrast, we find that genes with partial methylation tend to be constitutively expressed. These patterns contrast with those found previously in other eukaryotes. By going beyond plants, animals and fungi, this stramenopile methylome adds significantly to our understanding of the evolution of DNA methylation in eukaryotes.
ISSN: 2041-1723

hal-01545322
https://hal.archives-ouvertes.fr/hal-01545322
DOI : 10.1038/ncomms3091

Résumé : L’HTLV-1 est l’agent étiologique de la TSP/HAM et de l’ATL. La TSP/HAM est une méningomyélite chronique d’évolution lente et progressive. La charge provirale HTLV-1 est corrélée à l’évolutivité de la maladie. La protéine virale Tax module la synthèse et la fonction de multiples protéines de la prolifération et de la survie des lymphocytes T infectés. L’expression virale n’est pas toujours détectable in vivo. Une modulation épigénétique par inhibiteurs d’HDAC a été proposée. Des travaux dans le modèle du BLV et in vitro dans l’infection à HTLV-1 ont conforté ce concept et conduit à un essai thérapeutique évaluant le VPA dans le traitement de la TSP/HAM, qui n’a pas montré d’impact sur la charge provirale. Nous nous sommes intéressés à l’effet du VPA sur les lymphocytes T CD4+ en culture, cibles du virus HTLV-1. L’expression du génome viral, surtout la balance entre les protéines Tax et HBZ a été étudiée avec ou sans VPA. Son expression serait corrélée à la charge provirale et à l’évolution de la TSP/HAM. Nous montrons qu’un tiers des cellules CD4+ infectées expriment Tax. Cette proportion augmente sous VPA. La détection de la protéine p19 est augmentée sous VPA. La stimulation par le VPA de la transcription sens du génome viral a été confirmée par quantification des messagers Tax et Gag alors que l’expression d’HBZ se trouve réprimée sous VPA. Les données cinétiques d’expression spontanée d’HBZ montrent l’existence d’un rétrocontrôle négatif exercé par HBZ sur l’expression de Tax et des gènes structuraux. Influer sur l’expression d’HBZ ouvre une voie nouvelle pour le traitement des maladies associées à HTLV-1.
HTLV-1 is the etiological agent of HAM/TSP and ATL. TSP/HAM is a chronic meningomyelitis with a course being slow and progressive. HTLV-1 proviral load correlates with disease progression. Tax protein modulates the synthesis and function of proteins involved in the regulation of infected T-lymphocytes proliferation and survival. Viral expression is not always detectable in vivo. An epigenetic modulation by the use of HDAC inhibitors has been proposed. A study in the BLV model and an in vitro study in a HTLV-1 infection have lead to a therapeutic assay in order to assess VPA in the treatment of HAM/TSP. This assay did not show any impact on the proviral load. We evaluated the impact of VPA treatment on viral genome expression in cultured lymphocytes, especially the balance between Tax and HBZ. A third of provirus-positive CD4+ T cells spontaneously became Tax-positive. The estimation rose up to two-thirds of Tax-positive infected cells when VPA was added. VPA enhanced Gag p19 protein release. VPA treatment enhanced and prolonged Tax mRNA expression, while it blocked HBZ expression. Our data are consistent with the hypothesis of a feed-back loop coordinating Tax and HBZ expression. Modulation of HBZ expression may impact the net outcome of VPA treatment on HTLV-1-infected cell proliferation and survival.

http://www.theses.fr/2011AGUY0403