Epigenetic mechanisms involved in developmental nutritional programming

The ways in which epigenetic modifications fix the effects of early environmental events, ensuring sustained responses to transient stimuli, which result in modified gene expression patterns and phenotypes later in life, is a topic of considerable interest. This review focuses on recently discovered mechanisms and calls into question prevailing views about the dynamics, position and functions of epigenetic marks. Most epigenetic studies have addressed the long-term effects on a small number of epigenetic marks, at the global or individual gene level, of environmental stressors in humans and animal models. In parallel, increasing numbers of studies based on high-throughput technologies and focusing on humans and mice have revealed additional complexity in epigenetic processes, by highlighting the importance of crosstalk between the different epigenetic marks. A number of studies focusing on the developmental origin of health and disease and metabolic programming have identified links between early nutrition, epigenetic processes and long-term illness. The existence of a self-propagating epigenetic cycle has been demonstrated. Moreover, recent studies demonstrate an obvious sexual dimorphism both for programming trajectories and in response to the same environmental insult. Despite recent progress, we are still far from understanding how, when and where environmental stressors disturb key epigenetic mechanisms. Thus, identifying the original key marks and their changes throughout development during an individual’s lifetime or over several generations remains a challenging issue

Symposium 2: Modern approaches to nutritional research challenges. Nutritional developmental epigenomics: immediate and long-lasting effects: Nutritional developmental epigenomics: immediate and long-lasting effects

International audienceThe phenotype of an individual is the result of complex interactions between genome, epigenome and current, past and ancestral environment leading to a lifelong remodelling of the epigenomes. The genetic information expression contained in the genome is controlled by labile chromatin-associated epigenetic marks. Epigenetic misprogramming during development is widely thought to have a persistent effect on the health of the offspring and may even be transmitted to the next generation. The epigenome serves as an interface between the environment and the genome. Dietary factors, including folate involved in C1 metabolism, and other social and lifestyle exposures have a profound effect on many aspects of health including ageing and do so, at least partly, through interactions with the genome, which result in altered gene expression with consequences for cell function and health throughout the life course. Depending on the nature and intensity of the environmental insult, the critical spatiotemporal windows and developmental or lifelong processes involved, epigenetic alterations can lead to permanent changes in tissue and organ structure and function or to phenotypic changes that can (or cannot) be reversed using appropriate epigenetic tools. Moreover, the flexibility of epigenetic marks may make it possible for environmental, nutritional and hormonal factors or endocrine disruptors to alter, during a particular spatiotemporal window in a sex-specific manner, the sex-specific methylation or demethylation of specific CpG and/or histone modifications underlying sex-specific expression of a substantial proportion of genes. Moreover, genetic factors, the environment and stochastic events change the epigenetic landscape during the lifetime of an individual. Epigenetic alterations leading to gene expression dysregulation accumulate during ageing and are important in tumorigenesis and age-related diseases. Several encouraging trials suggest that prevention and therapy of age- and lifestyle-related diseases by individualised tailoring to optimal epigenetic diets or drugs are conceivable. However, these interventions will require intense efforts to unravel the complexity of these epigenetic, genetic and environment interactions and to evaluate their potential reversibility with minimal side effects

Le dimorphisme sexuel au XXIe siècle

A new definition of sexual dimorphism is required. The divergent biology of the sexes is still largely ignored, overshadowed by sociocultural considerations and confined to its hormonal organizational and activational effects, while the genes unequally expressed by the sex chromosomes play an important role much earlier, after conception, to set the stage and throughout life. These different components have independent and parallel effects that can interact in a synergistic or antagonistic manner on differentiation and response processes to trigger or erase sex-specific differences. The epigenetic marks and machinery represent the perfect tools to keep the memory of which sex is ours from the very beginning of life. Within the context of the developmental origin of adult health and diseases (DOHaD), owing to their flexibility to the environment, epigenetic marks also represent a support to archive the effects of environments during development, according to the sex of the parent, in a sex-specific mode. In all tissues, including gonads and brain, different trajectories of genes and pathways are used at the basal levels and to modulate/dictate responses according to sex and gender. It is urgent to emphasize the need to take into consideration this new knowledge and to apply less sex-biased approaches in research, medicine and society, to enhance women health and well-being. A critical review and realization of gender-specific social constraints, an indeniably but slowly on-going process, should allow us to "set free our sex biology" while detracting the delusion of hierarchy of the complex mechanisms involved.En ce début du XXIe siècle, une redéfinition du dimorphisme sexuel s’impose. Elle se doit d’incorporer conjointement non seulement les hormones sexuelles et le formatage socio culturel spécifique du genre, mais aussi l’importance des gènes localisés sur les chromosomes sexuels. Ces différentes composantes ont des effets indépendants et parallèles et qui interagissent dès la conception et tout au long de la vie. Des mécanismes épigénétiques assurent la mise en place de marques spécifiques du sexe qui modulent l’expression des gènes sans changer leur séquence. Ces marques représentent une sorte de mémoire pour se « souvenir » de son sexe, mais aussi pour « archiver » les impacts de l’environnement, selon l’expérience. Dans tous les tissus, ces marques et d’autres à venir, façonnées en fonction du sexe et du genre au gré de l’environnement, établissent des réseaux de gènes différents chez le mâle et la femelle, tant au niveau basal que pour les réponses immédiates et futures

Le modèle porcin naturel de retard de croissance pour l’étude de la programmation métabolique et l’obésité

Le retard de croissance intra-utérin (RCIU) demeure un problème non résolu en médicine périnatale. Le RCIU est reconnu comme une des causes principales de morbidité périnatale et résulte, entre autres, d’un mauvais environnement maternel et d’une insuffisance placentaire. L’environnement maternel inadéquat met en danger non seulement la vie du nouveau né mais a des répercussions à long terme sur la vie du futur adulte. Des études épidémiologiques ont en effet démontré que le RCIU est associé à un risque élevé de développement de pathologies tardives tels que l’hypertension, le diabète de type 2 et l’obésité. Cette association a donné lieu au concept bien connu de programmation métabolique développé par BARKER en 1994. De manière intéressante, les modèles animaux mimant la situation chez l’homme sont d’excellents outils pour comprendre les mécanismes génétiques, moléculaires et cellulaires sous jacents. Historiquement les petits rongeurs ont été les modèles prédominants d’étude de la programmation fœtale et plusieurs techniques ont été développées sur cette espèce pour induire expérimentalement des animaux RCIU. Récemment, le modèle porcin naturel de retard de croissance a été reconnu comme intéressant pour l’étude de la programmation métabolique et l’obésité. En effet, comme chez le RCIU humain, le porc RCIU présente les même signes de croissance adaptatrice/compensatrice entrainant une augmentation de l’adiposité au cours de la vie adulte. De plus, les processus de croissance et de développement des organes du porc sont semblables à ceux décrits chez l’Homme. En utilisant ce modèle, nous avons montré que quelques jours après la naissance les porcs RCIU présentent une altération de la distribution de l’expression du récepteur de la leptine au niveau des noyaux hypothalamiques. Nous avons observé une altération de la structure du tissu adipeux chez le porc RCIU avec une grande densité de petites cellules adipocytaires. Après le sevrage, les animaux accusent une croissance postnatale rapide entrainant une augmentation de l’adiposité à un âge plus avancé (J 165). Le traitement postnatal par la leptine inverse partiellement le phénotype de l’IUGR en corrigeant la vitesse de croissance, la composition corporelle et rétablit le poids et la structure de certains organes impliqués dans la régulation métabolique. Ces résultats pourraient contribuer au développement d’une nouvelle thérapie pour la lutte contre la programmation métabolique et le développement à long terme de l’obésité

Distribution différentielle des neurones hypothalamiques exprimant le récepteur à la leptine en fonction du poids à la naissance chez le porcelet

National audienc

Effets du blocage de la leptine au cours de l'installation des circuits neuronaux de contrôle de la prise alimentaire

National audienc

Effets du blocage de la leptine au cours de l'installation des circuits neuronaux de contrôle de la prise alimentaire

National audienc

Early post natal leptin blockage induced a long term leptin resistance in rats

International audienc

Early post natal leptin blockage induced a long term leptin resistance in rats

International audienc

Sexual dimorphism of hepatic epigenetic marks and machinery in offspring of obese and diabetic mothers fed a control diet during periconceptional/gestation/lactation period

National audienceEarly nutritional events may have an influence on later life health mainly through epigenetic processes.1 In our two- generation mice model, providing obese and diabetic mice with a control diet during the periconceptional/gestation/ lactation period led to a pronounced sex-specific shift from susceptibility to resistance to a high-fat diet (HFD) in the female offspring only.2,3 The aim of this study was to detect sex-specific differences in the expression of candidate genes and epigenetic marks and machinery in the liver of both sexes and both generations. As a key organ for lipid processing and detoxification, liver plays a major role in conditions of chronic lipid oversupply. According to the sex, female (F) or male (M), the generation, first (F1) or second (F2), and diet types, CD or HFD, mice were divided into eight groups (F-F1-CD, F-F1-HFD, M-F1-CD, M-F1-HFD, F-F2-CD, F-F2-HFD, M-F2-CD and M-F2-HFD). Body weight, blood glucose level and blood cholesterol levels were measured. Liver morphology was identified by hematoxylin–eosin staining and oil red O staining. Hepatosteatosis was found to be more common in all HFD groups with adaptation of the liver phenotype in F2 females but not in males, in parallel with obesity and cholesterol levels.4 Global DNA methyla- tion and histone modifications were investigated by LUMA and Western blot analysis, respectively. Interestingly, although no significant difference was found within groups, global DNA methylation level was significantly negatively correlated to steatosis percentage. Using RT-qPCR, sexual dimorphism was observed for the gene expression of 12 genes encoding enzymes of the epigenetic machinery. These marks may help us to understand the sex-specific epigenetic mechanisms of the underlying sex-specific responses to HFD and improve the early life nutritional environment in a sex-specific manner. The author(s) declare that they have no competing interests