Endotoxin-tolerante Zellen zeigen über mehrere Tage eine verminderte Produktion pro-inflammatorischer Zytokine, sodass epigenetische Veränderungen ein Grund für die Endotoxintoleranz sein könnte. Im 1. Teil wurden epigenetische Veränderungen an gezielten LPS-tolerisierbaren Genen mithilfe eines in-vitro-Modells mit humanen Monozyten untersucht. Die Gene kodierend für TNF und CXCL10 zeigten eine Reduktion der transkriptionsaktivierenden Histonmarker H3K27ac und H4ac, die durch eine stark reduzierte Genexpression in toleranten Monozyten begleitet wurde. Demgegenüber wiesen Gene wie IL6 und IL1B eine Zunahme an H4ac und H3K27ac auf, während ihre Genexpression in widersprüchlicher Weise reduziert war. Repressive epigenetische Marker (H3K9me2, H3K27me3, H4K20me3, DNA-Methylierung) konnten in den untersuchten Genen nicht nachgewiesen werden. Zudem war die IL6-Genexpression verstärkt abhängig von der Signaltransduktion toleranter Monozyten, was auf unterschiedliche Repressionsmechanismen schließen lässt. Im 2. Teil konnte gezeigt werden, dass die genomweite transkriptionelle Reprogrammierung durch eine globale Verschiebung von aktiven H3K27ac und H4ac in naiven Monozyten zu repressiven H3K9me2, H3K27me3 und H4K20me3 in toleranten, restimulierten Zellen einherging. Mehr als 10000 Genombereiche wiesen Veränderungen an Histonmarkern auf, obwohl nur 3638 Gene unterschiedlich exprimiert waren. Circa 27% der differentiell exprimierten Gene zeigten ein Expressionsmuster, welches mit Veränderungen an aktiven und/oder repressiven Markern innerhalb der Promoterregion korrelierte. Zudem zeigten intergenische Regionen einen verstärkten Anstieg an repressiven Histonmarkern, was auf eine mögliche regulatorische Funktion dieser Bereiche in der Endotoxintoleranz schließen lässt. Die Studie zeigt, dass die Epigenetik der Monozyten stark von der Endotoxintoleranzinduktion betroffen ist, wenn auch nicht alle Veränderungen dem beobachteten Genexpressionsmuster zugeordnet werden konnten. / Endotoxin-tolerant cells show a reduced ability to produce pro-inflammatory cytokines for several days, which assumes an impact of epigenetic changes in endotoxin tolerance induction. Using an in vitro model with human monocytes, the first part focused on the analysis of epigenetic changes in specific LPS-tolerizable genes. The genes encoding for TNF and CXCL10 showed a reduction in the transcription-activating histone marks H3K27ac and H4ac in tolerant monocytes, which was accompanied by a strongly reduced gene expression. In contrast, the IL6 and IL1B genes showed an increase in activating histone modifications, while their gene expressions were moderately reduced. Repressive epigenetic marks (H3K9me2, H3K27me3, H4K20me3, DNA methylation) were not specifically enhanced in the genes studied. Particularly the IL6 gene expression was more susceptible to the signaling strength in tolerant monocytes implying distinct mechanisms in the repression of the genes analyzed. Within the second part, genome-wide reprogramming of tolerant monocytes was accompanied by a global shift from activating H3K27ac and H4ac in naive monocytes to repressive H3K9me2, H3K27me3 and H4K20me3 in tolerant cells treated with LPS. More than 10000 genomic regions were distinctly regulated by histone marks, though only 3638 genes were differentially expressed. Correlation analyses identified 27 % of the differentially expressed genes that showed a transcriptional level consistent with changes in activating and/or repressive histone marks within their promoter regions. Intergenic regions were highly enriched for repressive histone marks in LPS-tolerant monocytes implying a regulatory function in endotoxin tolerance. The data indicate that the epigenetic environment of monocytes is highly affected by endotoxin tolerance induction, though not all changes are directly linked to the gene expression pattern observed.

It is evident that components of the 26S proteasome function beyond protein degradation in the regulation of transcription. Studies in yeast implicate the 26S proteasome, specifically the 19S cap, in the epigenetic regulation of transcription. Saccharomyces cerevisiae 19S ATPases remodel chromatin by facilitating histone acetylation and methylation. However, it is unclear if the 19S ATPases play similar roles in mammalian cells. We previously found that the 19S ATPase Sug1 positively regulates transcription of the critical inflammatory gene MHC-II and that the MHC-II promoter fails to efficiently bind transcription factors upon Sug1 knockdown. MHC-II transcription is regulated by the critical coactivator CIITA. We now find that Sug1 is crucial for regulating histone H3 acetylation at the cytokine inducible MHC-II and CIITA promoters. Histone H3 acetylation is dramatically decreased upon Sug1 knockdown with a preferential loss occurring at lysine 18. Research in yeast indicates that the ortholog of Sug1, Rpt6, acts as a mediator between the activating modifications of histone H2B ubiquitination and H3 methylation. Therefore, we characterized the role the 19S proteasome plays in regulating additional activating modifications. As with acetylation, Sug1 is necessary for proper histone H3K4 and H3R17 methylation at cytokine inducible promoters. In the absence of Sug1, histone H3K4me3 and H3R17me2 are substantially inhibited. Our observation that the loss of Sug1 has no significant effect on H3K36me3 implies that Sug1’s regulation of histone modifications is localized to promoter regions as H3K4me3 but not H3K36me3 is clustered around gene promoters. Here we show that multiple H3K4 histone methyltransferase subunits bind constitutively to the inducible MHC-II and CIITA promoters and that over-expressing one subunit significantly enhances promoter activity. Furthermore, we identified a critical subunit of the H3K4 methyltransferase complex that binds multiple histone modifying enzymes, but fails to bind the CIITA promoter in the absence of Sug1, implicating Sug1 in recruiting multi-enzyme complexes responsible for initiating transcription. Finally, Sug1 knockdown maintains gene silencing as elevated levels of H3K27 trimethylation are observed upon Sug1 knockdown. Together these studies strongly implicate the 19S proteasome in mediating the initial reorganization events to relax the repressive chromatin structure surrounding inducible genes.

Major Histocompatibility Complex Class-II (MHC-II) molecules are critical regulators of adaptive immunity that present extracellular antigens required to activate CD4+ T cells. MHC-II are regulated at the level of transcription by master regulator, the Class II Transactivator (CIITA), whose association with the MHC-II promoter is necessary to initiate transcription. Recently, much research focused on novel mechanisms of transcriptional regulation of critical genes like MHC-II and CIITA; findings that the macromolecular complex of the 26S-proteasome is involved in transcription have been perhaps the most exciting as they impart novel functions to a well studied system. Proteasome is a multi-subunit complex composed of a 20S-core particle capped by a 19S-regulatory particle. The 19S contains six ATPases which are required for transcription initiation and elongation. We demonstrate that 19S ATPase-S6a inducibly associates with CIITA promoters. Decreased expression of S6a negatively impacts recruitment of the transcription factors STAT-1 and IRF-1 to the CIITA due to significant loss in histone H3 and H4 acetylation. S6a is robustly recruited to CIITA coding regions, where S6a binding coordinates with that of RNA polymerase II. RNAi mediated S6a knockdown significantly diminishes recruitment of Pol II and P-TEF-b components to CIITA coding regions, indicating S6a plays important roles in transcriptional elongation. Our research is focused on the ways in which accessibility to and transcription of DNA is regulated. While cancers are frequently linked to dysregulated gene expression, contribution of epigenetics to cancers remains unknown. To achieve metastatic ability, tumors alter gene expression to escape host immunosurveilance. MHC-II and CIITA expression are significantly downregulated in highly metastatic MDA-MB-435 breast cancer cells. This suppression correlates with elevated levels of the silencing modification H3K27me3 at CIITA and a significant reduction in Pol II recruitment. We observe elevated binding of the histone methyltransferase to CIITApIV and demonstrate this enzyme is a master regulator of CIITA gene expression. EZH2 knockdown results in significant increases in CIITA and MHC-II transcript levels in metastatic cells. In sum, transcriptional regulation by the 19S-proteasome and histone modifying enzymes represents novel mechanisms of control of mammalian gene expression and present novel therapeutic targets for manipulating MHC expression in disease.

No description available.

Eukaryotic genomes are packed into the confines of the nucleus through a nucleoproteic structure called chromatin. Chromatin is a dynamic structure that can respond to developmental or environmental cues to regulate and orchestrate the functions of the genome. The fundamental unit of chromatin, the nucleosome, consists of a protein octamer, which contains two molecules of each of the core histone proteins (H2A, H2B, H3, H4), around which 147 bp of DNA is wrapped. The post-translational modifications (PTMs) of histones and methylation of the cytosine residues in DNA (DNA methylation) constitute primary epigenomic markers that dynamically alter the interaction of DNA with nucleosomes and participate in the regulation and control access to the underlying DNA. The main objective of my thesis was to understand the spatial and temporal dynamics of chromatin states in Arabidopsis by investigating on a genome-wide scale, patterns of DNA methylation and a set of well-characterized histone post-translational modifications. DNA methylation, a hallmark of epigenetic inactivation and heterochromatin in both plants and mammals, is largely confined to transposable elements and other repeat sequences. I show in this thesis that in Arabidopsis, methylated TE sequences having no or few matching siRNAs, and therefore unlikely to be targeted by the RNA-directed DNA methylation (RdDM) machinery, acquire DNA methylation through spreading from adjacent siRNA-targeted regions. Further, I propose that this spreading of DNA methylation through promoter regions can explain, at least in part, the negative impact of siRNA-targeted TE sequences on neighbouring gene expression. In a second part, I have contributed to integrative analysis of DNA methylation and eleven histone PTMs. I have shown through combinatorial and cluster analysis that the Arabidopsis epigenome shows simple principles of organisation and can be distinguished into four primary types of chromatin that preferentially index active genes, repressed genes, TEs, and intergenic regions. Finally, in a third part, I integrated epigenomics with transcriptome data at three different time points in a developmental window to investigate the temporal dynamics of chromatin states in response to an external stimulus. This used the light-induced transcriptional response as a paradigm to assess the impact of histone H2B monoubiquitination (H2Bub), and showed that this PTM is associated with active transcription and implicated in the selective fine-tuning of gene expression. Taken together, the work presented here contributes significantly to our understanding of the spatial organisation of chromatin states in plants, its dynamic nature and how it can contribute to allow plants to respond to a signal from the environment.

It is evident that components of the 26S proteasome function beyond protein degradation in the regulation of transcription. Studies in yeast implicate the 26S proteasome, specifically the 19S cap, in the epigenetic regulation of transcription. Saccharomyces cerevisiae 19S ATPases remodel chromatin by facilitating histone acetylation and methylation. However, it is unclear if the 19S ATPases play similar roles in mammalian cells. We previously found that the 19S ATPase Sug1 positively regulates transcription of the critical inflammatory gene MHC-II and that the MHC-II promoter fails to efficiently bind transcription factors upon Sug1 knockdown. MHC-II transcription is regulated by the critical coactivator CIITA. We now find that Sug1 is crucial for regulating histone H3 acetylation at the cytokine inducible MHC-II and CIITA promoters. Histone H3 acetylation is dramatically decreased upon Sug1 knockdown with a preferential loss occurring at lysine 18. Research in yeast indicates that the ortholog of Sug1, Rpt6, acts as a mediator between the activating modifications of histone H2B ubiquitination and H3 methylation. Therefore, we characterized the role the 19S proteasome plays in regulating additional activating modifications. As with acetylation, Sug1 is necessary for proper histone H3K4 and H3R17 methylation at cytokine inducible promoters. In the absence of Sug1, histone H3K4me3 and H3R17me2 are substantially inhibited. Our observation that the loss of Sug1 has no significant effect on H3K36me3 implies that Sug1’s regulation of histone modifications is localized to promoter regions as H3K4me3 but not H3K36me3 is clustered around gene promoters. Here we show that multiple H3K4 histone methyltransferase subunits bind constitutively to the inducible MHC-II and CIITA promoters and that over-expressing one subunit significantly enhances promoter activity. Furthermore, we identified a critical subunit of the H3K4 methyltransferase complex that binds multiple histone modifying enzymes, but fails to bind the CIITA promoter in the absence of Sug1, implicating Sug1 in recruiting multi-enzyme complexes responsible for initiating transcription. Finally, Sug1 knockdown maintains gene silencing as elevated levels of H3K27 trimethylation are observed upon Sug1 knockdown. Together these studies strongly implicate the 19S proteasome in mediating the initial reorganization events to relax the repressive chromatin structure surrounding inducible genes.

La poly(ADP-ribosyl)ation est une modification post-traductionnelle des protéines par les poly(ADP-ribose) polymérases (PARPs). PARP3 a été identifiée comme un nouvel acteur de la réparation des cassures double-brin (DSBs). Nous avons évalué la contribution de PARP3 dans les différentes voies de réparation (HR, C-NHEJ ou A-EJ). Les résultats obtenus définissent PARP3 comme un modulateur de l’étape de résection d’ADN simple-brin permettant d’engager le choix de la voie de réparation. Nous avons montré que PARP3 favorise le recrutement du complexe Ku70/Ku80 aux sites de cassures et module la balance BRCA1/53BP1. Ces deux événements limitent l’étape de réparation de la voie HR et A-EJ et oriente la réparation vers la voie du C-NHEJ. Par immunoprécipitation de la chromatine, nous avons étudié les conséquences de l’absence de PARP3 sur les modifications d’histones, connues pour moduler la décision entre les différentes voies de réparation. Nos résultats actuels ne nous ont pas permis d’établir de lien entre PARP3 et les modifications d’histones en réponse aux DSBs. Nous avons toutefois observé qu’en absence de dommages, l’absence de PARP3 induit un enrichissement de H3K36me2 une marque d’histone connue pour réguler les gènes transcriptionnellement actifs. Dans un second projet, nous avons étudié l’impact de l’absence de PARP3 sur la viabilité cellulaire et la progression tumorale de cellules cancéreuses mutées en BRCA1. Nous avons montré par des approches in vitro et in vivo que l’absence de PARP3 induit une diminution de la survie et de la prolifération cellulaire plus marquée, une amplification exacerbée des centrosomes, ainsi qu’un ralentissement plus important de la progression tumorale, faisant de PARP3 une cible prometteuse en thérapie du cancer. / Poly(ADP-ribosyl)ation is a post-translational modification of proteins catalyzed by poly(ADPribose) polymerases (PARPs). PARP3 was identified as a novel actor of the double-strand break (DSBs) repair pathway. We evaluated the contribution of PARP3 in these repair pathways(HR, C-NHEJ ou A-EJ). Our results defined PARP3 as a modulator of the single strand DNA resection process which plays a role in driving the repair pathway choice. We showed that PARP3 enhances the recruitement of the Ku70/Ku80 complexe to damaged sites and modulates the BRCA1/53BP1 balance. These two events prevent the DNA end resection step initiating HR and A-EJ and drives the repair towards the C-NHEJ. By chromatin immunoprecipitation, we studied the consequences of the absence of PARP3 on histone modifications, known to modulate the decision of the DSBs repair pathways. Our current results didn’t allow us to establish a link between PARP3 and histone modifications in response to DSBs. However, in absence of DNA damage and PARP3, we observed an accumulation of H3K36me2, a histone mark known to regulate transcriptionally active genes. In a second project, we studied the impact of the absence of PARP3 on cell viability and tumor progression in breast cancer cell lines mutated in BRCA1. By in vitro and in vivo approaches, we showed that the absence of PARP3 induces an important decrease in cell survival and proliferation, an increase in centrosomal amplification and a strong delay in tumor progression. The roles of PARP3 in both cellular response to DNA damage and mitotic progression introduce PARP3 as a possible promising therapeutic target in cancer therapy.

Les génomes nucléaires eucaryotes sont empaquetés au sein d’une structure nucléoprotéique appelée chromatine et dont l’unité fondamentale est le nucléosome. Celui-ci est composé d’un octamère d’histones, contenant deux molécules de chacune des histones H2A, H2B, H3 et H4, autour duquel 147 pb d’ADN sont enroulées. Les modifications post-traductionnelles (PTMs) des histones et de l’ADN (méthylation des cytosines) constituent des marqueurs épigénomiques primaires qui participent à la régulation et au contrôle de l’accessibilité des différentes régions du génome. Ainsi, la chromatine forme une structure dynamique influencée par les changements environnementaux et développementaux et contribue à orchestrer diverses fonctions du génome. L’objectif principal de ma thèse était de caractériser l’organisation spatiale et la dynamique temporelle des états chromatiniens chez Arabidopsis par des approches à l’échelle du génome permettant l’étude des profils de méthylation de l’ADN et d’un ensemble de modifications post-traductionnelles des histones. La méthylation de l’ADN, une marque caractéristique de l’inactivation épigénétique et de l’hétérochromatine chez les plantes et les mammifères, est largement confinée aux séquences répétées, dont les éléments transposables (TEs). Par mon travail de thèse, j’ai montré que chez Arabidopsis les séquences de TEs faiblement méthylées ou non associées à des petits ARN interférents (siRNAs), donc potentiellement non régulées par la machinerie de RNA-directed DNA methylation (RdDM), peuvent acquérir une méthylation de l’ADN par diffusion à partir de séquences adjacentes ciblées par les siRNAs. Cette diffusion de la méthylation de l’ADN sur des régions promotrices pourrait expliquer, au moins en partie, l’impact négatif des TEs associés à des siRNAs sur l’expression des gènes à proximité immédiate. Dans une seconde partie de ma thèse, j’ai contribué à l’analyse intégrée de la méthylation de l’ADN et de onze modifications des histones. L’utilisation d’analyses combinatoires et en cluster m’a permis de montrer que l’épigénome d’Arabidopsis présente des principes simples d’organisation. En effet, ces analyses nous ont conduit à distinguer quatre états fondamentaux de la chromatine chez Arabidopsis, préférentiellement associés aux gènes actifs, aux gènes inactifs, aux TEs et aux régions intergéniques. Dans une troisième partie, j’ai intégré des données épigénomiques et transcriptomiques obtenues à différents temps afin d’étudier les dynamiques temporelles des états chromatiniens en réponse à un stimulus externe, la première exposition à la lumière des plantules suite à la germination. Ces travaux nous ont permis de montrer que la monoubiquitination de l’histone H2B participe à la modulation fine et sélective des changements rapides de l’expression de gènes. L’ensemble du travail présenté contribue à une meilleure compréhension de l’organisation de la chromatine le long du génome des plantes et de la dynamique des états chromatiniens en réponse aux changements de l’environnement. / Eukaryotic genomes are packed into the confines of the nucleus through a nucleoproteic structure called chromatin. Chromatin is a dynamic structure that can respond to developmental or environmental cues to regulate and orchestrate the functions of the genome. The fundamental unit of chromatin, the nucleosome, consists of a protein octamer, which contains two molecules of each of the core histone proteins (H2A, H2B, H3, H4), around which 147 bp of DNA is wrapped. The post-translational modifications (PTMs) of histones and methylation of the cytosine residues in DNA (DNA methylation) constitute primary epigenomic markers that dynamically alter the interaction of DNA with nucleosomes and participate in the regulation and control access to the underlying DNA. The main objective of my thesis was to understand the spatial and temporal dynamics of chromatin states in Arabidopsis by investigating on a genome-wide scale, patterns of DNA methylation and a set of well-characterized histone post-translational modifications. DNA methylation, a hallmark of epigenetic inactivation and heterochromatin in both plants and mammals, is largely confined to transposable elements and other repeat sequences. I show in this thesis that in Arabidopsis, methylated TE sequences having no or few matching siRNAs, and therefore unlikely to be targeted by the RNA-directed DNA methylation (RdDM) machinery, acquire DNA methylation through spreading from adjacent siRNA-targeted regions. Further, I propose that this spreading of DNA methylation through promoter regions can explain, at least in part, the negative impact of siRNA-targeted TE sequences on neighbouring gene expression. In a second part, I have contributed to integrative analysis of DNA methylation and eleven histone PTMs. I have shown through combinatorial and cluster analysis that the Arabidopsis epigenome shows simple principles of organisation and can be distinguished into four primary types of chromatin that preferentially index active genes, repressed genes, TEs, and intergenic regions. Finally, in a third part, I integrated epigenomics with transcriptome data at three different time points in a developmental window to investigate the temporal dynamics of chromatin states in response to an external stimulus. This used the light-induced transcriptional response as a paradigm to assess the impact of histone H2B monoubiquitination (H2Bub), and showed that this PTM is associated with active transcription and implicated in the selective fine-tuning of gene expression. Taken together, the work presented here contributes significantly to our understanding of the spatial organisation of chromatin states in plants, its dynamic nature and how it can contribute to allow plants to respond to a signal from the environment.

La méthylation de l'ADN est l’une des marques épigénétiques les plus étudiées et est largement conservée. Mes travaux de thèse présentent le premier méthylome d'une diatomée marine P. tricornutum qui appartient à la famille des Stramenopiles. P. tricornutum présente une méthylation d’environ 6% qui est présente en mosaïque sur l’ensemble du génome. Une méthylation importante a été retrouvé chez les éléments transposables, en particulier les éléments amplifiés récemment de type Copia. L’analyse met en évidence plus de 320 gènes méthylés dans trois contextes génomiques différents : à proximité des éléments transposables, en grappes de gènes méthylés, et dans des gènes uniques. En outre, les gènes largement et complètement méthylés ont été trouvé fortement corrélés avec le silencing transcriptionnel et l'expression différentielle dans des conditions spécifiques. Enfin, il a été constaté que les gènes susceptibles d’avoir été acquis par transfert horizontal de gènes bactériens étaient préférentiellement insérés dans des régions riches en éléments transposables, ce qui suggère un mécanisme par lequel l'expression de gènes étrangers peut être tamponnée à la suite de leur insertion dans le génome. En résumé, P. tricornutum a une faible méthylation de l'ADN et une methylation relativement importante des éléments transposables et seulement quelques gènes méthylés. Ce premier méthylome d’une diatomée Stramenopile ajoute de manière significative à notre compréhension de l'évolution de la méthylation de l'ADN chez les eucaryotes. En ce qui concerne les modifications des histones, la distribution des marques H3K4me2, H3K9me2 et H3K27me3 a été examinée chez P. tricornutum. H3K4me2 est principalement associée à des gènes alors que les deux marques H3K9me2 et H3K27me3 ciblent principalement des éléments transposables. La répartition de H3K27me3 est inhabituelle et différente de ce qui a été observé chez les espèces modèles étudiées à ce jour. Les gènes marqués par H3K27me3 ont tendance à être faiblement exprimés et de façon différentielle. H3K27me3 et H3K9me2 ont tendance à co-marquer non seulement les éléments transposables méthylés, mais aussi des gènes fortement méthylés, ce qui semble être important pour le maintien du silencing des gènes différentiellement exprimés. L'analyse combinatoire de différentes marques d’histones et la méthylation de l'ADN nous a donné un aperçu du paysage de la chromatine chez les diatomées, et aidera à définir les caractéristiques structurales et fonctionnelles conservées. / DNA methylation is the most extensively studied and widely conserved epigenetic mark. Here the first whole genome methylome from a stramenopile, the marine model diatom P. tricornutum is reported. In P. tricornutum, around 6% of the genome was methylated in a mosaic landscape. Extensive methylation in transposable elements (TEs), especially in recently amplified Copia-like elements was found. Over 320 genes were found methylated occurring in three different genomic contexts: in the proximity of TEs, in clusters of methylated genes, and in single genes. Furthermore, genes extensively and completely methylated correlated strongly with transcriptional silencing and differential expression under specific conditions. Finally, it was found that genes likely acquired by horizontal gene transfer from bacteria were preferentially inserted within TE-rich regions, suggesting a mechanism whereby the expression of foreign genes can be buffered following their insertion in the genome. In general, P. tricornutum has low DNA methylation with relatively extensive DNA methylation on TEs and a few methylated genes. This first Stramenopile methylome adds significantly to our understanding of the evolution of DNA methylation in eukaryotes. As for the histone modifications, genome wide distribution of H3K4me2, H3K9me2 and H3K27me3 were examined in P. tricornutum. H3K4me2 is mainly associated with genes while both H3K9me2 and H3K27me3 marks target mainly transposable elements (TEs). The distribution of H3K27me3 is unusual and different from what have been profiled in model species so far. The genes marked by H3K27me3 tend to be lowly and differentially expressed. H3K27me3 and H3K9me2 tend to co-mark not only methylated TEs but also heavily methylated genes, which appears to be important for maintaining the silencing of differentially expressed genes. The combinatorial analysis of different histone marks and DNA methylation gave us an overview of diatom chromatin landscapes, and will help to define conserved structural and functional features.

L’origine de la variabilité phénotypique est un sujet très débattu depuis les théories de Lamarck et Darwin. Dans la vision contemporaine de l’évolution adaptative, il est communément admis que la seule source héritable de variabilité phénotypique soit d’origine génétique. Le phénotype est alors le produit du génotype sous l’influence de l’environnement. La mutation aléatoire des séquences d’ADN permet de générer de nouveaux variants phénotypiques qui sont alors soumis à la sélection naturelle. Traditionnellement, il est considéré que les caractères acquis par un individu durant sa vie, en réponse à l’environnement, ne sont pas héritables et ne jouent aucun rôle évolutif. Pourtant, il y a presque un siècle, un biologiste allemand du nom de Victor Jollos a mis en évidence que certains phénotypes peuvent être induits par des conditions environnementales particulières et persister durant quelques générations en l’absence du stimulus initial avant de disparaître progressivement. Il nomma ce phénomène Dauermodifikations, littéralement « modifications de longue durée ». Ses conclusions allaient à contre-courant des conceptions évolutives de son temps, et ont été considérées comme des artéfacts expérimentaux. Toutefois, nous sommes maintenant conscient qu’outre le code génétique, il existe également un autre mécanisme permettant une réponse héritable et pourtant flexible en réponse aux fluctuations environnementales : le code épigénétique. Au cours de cette thèse, j’ai essayé de mieux caractériser le rôle des mécanismes épigénétiques, plus précisément ceux impliques dans la structure chromatinienne, chez deux organismes présentant des Dauermodifikations : le corail tropical Pocillopora damicornis et le parasite humain Schistosoma mansoni. Les deux objectifs principaux de cette étude sont de déterminer (I) de quelle manière l’environnement influence la structure chromatinienne (ciblée ou aléatoire) et (II) dans quelle mesure ces changements sont-ils héritables (mitotiquement ou méïotiquement).Nos résultats ont permis de mieux caractériser les épigénomes des deux organismes étudiés. Nous avons décrit la structure chromatinienne de S. mansoni au travers de la distribution de six modifications d’histones, sur deux stades développementaux. Par ailleurs, nous avons montré chez S. mansoni trois types de changements de la structure chromatinienne : (I) ciblés en réponse à l’environnement, (II) associés au génotype et (III) aléatoires. Seuls les types II et III sont héritables d’un stade développemental du parasite à un autre. Nos travaux sur P. damicornis ont permis de remarquer une structure chromatinienne inhabituelle et d’offrir une première description d’un méthylome de corail. / The origin of phenotypic variability has been much debated since the establishment of Lamarck’s and Darwins theories of evolution. It is commonly accepted in the contemporary vision of adaptive evolution that the only source of heritable phenotypic variability is genetic. Here, phenotypes are the product of the genotypes under the influence of the environment. Random DNA mutations generate novel phenotypes, which are then subjected to natural selection. Traditionally, it is considered that acquired characters are not heritable and have no impact on evolution. Yet almost a century ago, a German biologist named Victor Jollos revealed that some phenotypes could be produced in particular environmental conditions and could persist for a few generations in the absence of the original stimulus, before disappearing gradually. He named this phenomenon Dauermodifikations, literally “long term changes”. His conclusions were going against evolutionary conceptions of his time, and were considered experimental artefacts. However, we are now aware that, in addition to the genetic code, there is also another heritable, and yet flexible, mechanism responding to environmental fluctuations: the epigenetic code. In this thesis, I attempted to characterize the role of epigenetic mechanisms, and more specifically modifications of the chromatin structure, in two organisms with Dauermodifikations: the tropical coral Pocillopora damicornis and the human parasite Schistosoma mansoni. The two main objectives of this study were (I) to determine how the environment influences the chromatin structure (in a targeted or random fashion) and (II) to what extent these changes are heritable (through mitosis or meiosis).My results provide a better knowledge of the epigenome of the two organisms we studied. We have described the chromatin structure of S. mansoni through the distribution of six histones modifications, in two developmental stages. Furthermore, we have shown three types of changes in chromatin structure of S. mansoni: (I) targeted in response to environmental changes, (II) genotype associated, and (III) random. Only types II and III are inherited to the next developmental stages of the parasite. Our work on P. damicornis delivers evidence for an unusual chromatin structure in this organism and to provide the first description of a coral methylome