Catherine Gallou-Kabani

Sex- and diet-specific changes of imprinted gene expression and DNA methylation in mouse placenta under a high-fat diet.

Background Changes in imprinted gene dosage in the placenta may compromise the prenatal control of nutritional resources. Indeed monoallelic behaviour and sensitivity to changes in regional epigenetic state render imprinted genes both vulnerable and adaptable. Methods and Findings We investigated whether a high-fat diet (HFD) during pregnancy modified the expression of imprinted genes and local and global DNA methylation patterns in the placenta. Pregnant mice were fed a HFD or a control diet (CD) during the first 15 days of gestation. We compared gene expression patterns in total placenta homogenates, for male and female offspring, by the RT-qPCR analysis of 20 imprinted genes. Sexual dimorphism and sensitivity to diet were observed for nine genes from four clusters on chromosomes 6, 7, 12 and 17. As assessed by in situ hybridization, these changes were not due to variation in the proportions of the placental layers. Bisulphite-sequencing analysis of 30 CpGs within the differentially methylated region (DMR) of the chromosome 17 cluster revealed sex- and diet-specific differential methylation of individual CpGs in two conspicuous subregions. Bioinformatic analysis suggested that these differentially methylated CpGs might lie within recognition elements or binding sites for transcription factors or factors involved in chromatin remodelling. Placental global DNA methylation, as assessed by the LUMA technique, was also sexually dimorphic on the CD, with lower methylation levels in male than in female placentae. The HFD led to global DNA hypomethylation only in female placenta. Bisulphite pyrosequencing showed that neither B1 nor LINE repetitive elements could account for these differences in DNA methylation. Conclusions A HFD during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes important in the control of many cellular, metabolic and physiological functions potentially involved in adaptation and/or evolution. These findings highlight the importance of studying both sexes in epidemiological protocols and dietary interventions.

Maternal Diets Trigger Sex-Specific Divergent Trajectories of Gene Expression and Epigenetic Systems in Mouse Placenta

Males and females responses to gestational overnutrition set the stage for subsequent sex-specific differences in adult onset non communicable diseases. Placenta, as a widely recognized programming agent, contibutes to the underlying processes. According to our previous findings, a high-fat diet during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes. We further investigated the impact of diet and sex on placental histology, transcriptomic and epigenetic signatures in mice. Both basal gene expression and response to maternal high-fat diet were sexually dimorphic in whole placentas. Numerous genes showed sexually dimorphic expression, but only 11 genes regardless of the diet. In line with the key role of genes belonging to the sex chromosomes, 3 of these genes were Y-specific and 3 were X-specific. Amongst all the genes that were differentially expressed under a high-fat diet, only 16 genes were consistently affected in both males and females. The differences were not only quantitative but remarkably qualitative. The biological functions and networks of genes dysregulated differed markedly between the sexes. Seven genes of the epigenetic machinery were dysregulated, due to effects of diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d, which could mark differently male and female epigenomes. The DNA methyltransferase cofactor Dnmt3l gene expression was affected, reminiscent of our previous observation of changes in global DNA methylation. Overall, this striking sexual dimorphism of programming trajectories impose a considerable revision of the current dietary interventions protocols.

Nutri-epigenomics: lifelong remodelling of our epigenomes by nutritional and metabolic factors and beyond.

Abstract The phenotype of an individual is the result of complex interactions between genotype, epigenome and current, past and ancestral environment, leading to lifelong remodelling of our epigenomes. Various replication-dependent and -independent epigenetic mechanisms are involved in developmental programming, lifelong stochastic and environmental deteriorations, circadian deteriorations, and transgenerational effects. Several types of sequences can be targets of a host of environmental factors and can be associated with specific epigenetic signatures and patterns of gene expression. Depending on the nature and intensity of the insult, the critical spatiotemporal windows and developmental or lifelong processes involved, these epigenetic alterations can lead to permanent changes in tissue and organ structure and function, or to reversible changes using appropriate epigenetic tools. Given several encouraging trials, prevention and therapy of age- and lifestyle-related diseases by individualised tailoring of 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. Clin Chem Lab Med 2007;45:321–7.

Sexual Dimorphism in Non-Mendelian Inheritance

There is accumulating evidence for nongenetic transgenerational inheritance with conspicuous marked sexual dimorphism for both the modes of transmission and the effects. Given the critical spatiotemporal windows, the role of the sex chromosomes, the regulatory pathways underlying sexual differentiation during gonad and brain development, and other developmental processes, as well as the lifelong impact of sex hormones, it is not surprising that most of the common diseases, which often take root in early development, display some degree of sex bias. The flexibility of epigenetic marks may make it possible for environmental and nutritional factors, or endocrine disruptors to alter—during a particular spatiotemporal window in a sex-specific manner—the sex-specific methylation or demethylation of specific CpGs and histone/chromatin modifications underlying sex-specific expression of a substantial proportion of genes. Thus, finely tuned developmental program aspects, specific to one sex, may be more sensitive to specific environmental challenges, particularly during developmental programming and gametogenesis, but also throughout the individuals life under the influence of sex steroid hormones. This review highlights the importance of studying both sexes in epidemiologic protocols or dietary interventions both in humans and in experimental models in animals.

Lifelong Circadian and Epigenetic Drifts in Metabolic Syndrome

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. However, little is known about the stochastically, genetically and environmentally triggered epimutations occurring during an individual’s lifetime. They may result from replication-dependent, replication-independent or DNA repair events. The rhythmic, circadian induction of a substantial proportion of genes, by a network of clock genes - one of which is a histone acetyl transferase - nuclear receptors and transcription factors is controlled by chromatin remodeling. The associated circadian epigenetic patterns must be transient, sensitive to environmental cues and reversible. Links have been found between circadian rhythms and major components of energy homeostasis, thermogenesis and hunger-satiety, rest-activity rhythms, and the sleep-wake cycle. Thus poorly adapted behavior or lifestyle and desynchronized cues may disturb the modulation of gene expression. This functional asynchrony may ultimately lead to persistence of aberrant and unphased “locking” or “leakage” of gene expression and inadapted responses in the body as a whole.

Epigénomique nutritionnelle : impact de régimes alimentaires déséquilibrés sur les processus épigénétiques de programmation au cours de la vie et transgénérationnels

Les modifications epigenetiques - associant une methylation de l’ADN et des modifications des histones - assurent par un remodelage adequat de la chromatine la modulation de l’expression des genes. Ces modifications sous-tendent la programmation, au cours du developpement fœtal et postnatal, aboutissant au faconnage des tissus et des organes. Outre l’heritage d’un genotype d’epargne les individus avec les desordres metaboliques conduisant au syndrome metabolique, a l’obesite, au diabete de type 2 et aux maladies cardiovasculaires ont subi au cours de fenetres critiques du developpement une « programmation epigenetique » anormale en liaison avec les desequilibres nutritionnels et les defauts metaboliques de la mere pendant la gestation et la lactation. Une programmation erronee peut avoir des effets sur la sante de l’enfant et surtout plus tard a l’age adulte et pourrait meme etre transmise a la generation suivante. Les marques et processus epigenetiques et en particulier celles portees par les transposons et les genes soumis a empreinte sont, du fait de leur labilite, hautement sensibles aux agents environnementaux et en particulier a l’alimentation et, en principe, reversibles. Elles jouent donc un role crucial au cours du developpement et de l’evolution. Dans cette revue, nous decrivons brievement les consequences physiopathologiques, a l’age adulte, des conditions nutritionnelles influencant les principales etapes de la programmation epigenetique au cours du developpement fœto-placentaire et post-natal, les coadaptations evolutives des generations et les effets trans-generationnels, ainsi que les principaux objectifs actuels de recherche.