A Sustained Dietary Change Increases Epigenetic Variation in Isogenic Mice

Epigenetic changes can be induced by adverse environmental exposures, such as nutritional imbalance, but little is known about the nature or extent of these changes. Here we have explored the epigenomic effects of a sustained nutritional change, excess dietary methyl donors, by assessing genomic CpG methylation patterns in isogenic mice exposed for one or six generations. We find stochastic variation in methylation levels at many loci; exposure to methyl donors increases the magnitude of this variation and the number of variable loci. Several gene ontology categories are significantly overrepresented in genes proximal to these methylation-variable loci, suggesting that certain pathways are susceptible to environmental influence on their epigenetic states. Long-term exposure to the diet (six generations) results in a larger number of loci exhibiting epigenetic variability, suggesting that some of the induced changes are heritable. This finding presents the possibility that epigenetic variation within populations can be induced by environmental change, providing a vehicle for disease predisposition and possibly a substrate for natural selection

Sex- and Diet-Specific Changes of Imprinted Gene Expression and DNA Methylation in Mouse Placenta under a High-Fat Diet

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

Épigénomique nutritionnelle du syndrome métabolique

The importance of epigenetic alterations has been acknowledged in cancer for about two decades by an increasing number of molecular oncologists who contributed to deciphering the epigenetic codes and machinery and opened the road for a new generation of drugs now in clinical trials. However, the relevance of epigenetics to common diseases such as metabolic syndrome and cardiovascular disease was less conspicuous. This review focuses on converging data supporting the hypothesis that, in addition to "thrifty genotype" inheritance, individuals with metabolic syndrome (MetS)--combining disturbances in glucose and insulin metabolism, excess of predominantly abdominally distributed weight, mild dyslipidemia and hypertension, with the subsequent development of obesity, type 2 diabetes mellitus (T2D) and cardiovascular disease (CVD)--have suffered improper "epigenetic programing" during their fetal/postnatal development due to maternal inadequate nutrition and metabolic disturbances and also during their life-time. Moreover, as seen for obesity and T2D, MetS tends to appear earlier in childhood, to be more severe from generation to generation and to affect more pregnant women. Thus, in addition to maternal effects, MetS patients may display "transgenerational effects" via the incomplete erasure of epigenetic marks endured by their parents and grandparents. We highlight the susceptibility of epigenetic mechanisms controlling gene expression to environmental influences due to their inherent malleability, emphasizing the participation of transposable elements and the potential role of imprinted genes during critical time windows in epigenetic programming, from the very beginning of development throughout life. Increasing our understanding on epigenetic patterns significance and small molecules (nutrients, drugs) that reverse epigenetic (in) activation should provide us with the means to he obsolete human thrifty genotype into a "squandering" phenotype

Sex-specific changes in placental gene expression and epigenetic pattern induced by maternal high fat diet

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Dietary alleviation of maternal obesity and diabetes: increased resistance to diet-induced obesity transcriptional and epigenetic signatures.

According to the developmental origins of health and diseases (DOHaD), and in line with the findings of many studies, obesity during pregnancy is clearly a threat to the health and well-being of the offspring, later in adulthood. We previously showed that 20% of male and female inbred mice can cope with the obesogenic effects of a high-fat diet (HFD) for 20 weeks after weaning, remaining lean. However the feeding of a control diet (CD) to DIO mice during the periconceptional/gestation/lactation period led to a pronounced sex-specific shift (17% to 43%) from susceptibility to resistance to HFD, in the female offspring only. Our aim in this study was to determine how, in the context of maternal obesity and T2D, a CD could increase resistance on female fetuses. Transcriptional analyses were carried out with a custom-built mouse liver microarray and by quantitative RT-PCR for muscle and adipose tissue. Both global DNA methylation and levels of pertinent histone marks were assessed by LUMA and western blotting, and the expression of 15 relevant genes encoding chromatin-modifying enzymes was analyzed in tissues presenting global epigenetic changes. Resistance was associated with an enhancement of hepatic pathways protecting against steatosis, the unexpected upregulation of neurotransmission-related genes and the modulation of a vast imprinted gene network. Adipose tissue displayed a pronounced dysregulation of gene expression, with an upregulation of genes involved in lipid storage and adipocyte hypertrophy or hyperplasia in obese mice born to lean and obese mothers, respectively. Global DNA methylation, several histone marks and key epigenetic regulators were also altered. Whether they were themselves lean (resistant) or obese (sensitive), the offspring of lean and obese mice clearly differed in terms of several metabolic features and epigenetic marks suggesting that the effects of a HFD depend on the leanness or obesity of the mother

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. © 2012 Gabory et al

Phenotypic and metabolic characteristics of the mice after 24 weeks on the CD and HFD, for the F1LM (CD1, OP1 and OR1) and F2OM (CD2, OP2 and OR2) mice.

<p>The values presented are the means±SEM. For weight and caloric intake, <i>n</i> = 50 to 70, for plasma hormone and metabolite determinations, <i>n</i> = 10 to 15, for FA level determination, <i>n</i> = 7, and for Piximus analysis and organ weights, <i>n</i> = 5.</p>a<p><i>p</i><0.05 for comparison with control,</p>b<p><i>p</i><0.05 for comparison between OP and OR mice,</p>c<p><i>p</i><0.05 for comparison between the F1LM and F2OM mice, assessed by Kruskal-Wallis tests followed by Dunn’s <i>post hoc</i> tests.</p

Schematic diagram summarizing the transcriptional data obtained for the liver, muscle and adipose tissue and the results of epigenetic studies in OP1, OP2 and OR2 mice.

<p>Blue arrows represent potential lipid fluxes. In the hyperphagic OP1 and OP2 mice, lipid ingestion was much greater than in OR2 mice, in which caloric intake was normalized. In OP mice, excess lipids were initially stored in the adipose tissue, leading to adipocyte hypertrophy in OP1 mice and hyperplasia in OP2 mice, as a function of the level of expression of <i>Lep</i> and <i>Peg1</i>. In OR2 mice, lipids were stored in the adipose tissue without adipocyte abnormalities or ectopic storage, as in mice supplied with limited amounts of lipid. In OP1 mice, the excess lipids were stored in the liver, contributing to hepatic hypertrophy. Transcriptomic data indicated that <i>de novo</i> lipogenesis was activated in OP1 mice and that insulin signaling was greatly disturbed. In OP2 mice, genes related to insulin signaling were less affected, whereas genes involved in fatty acid oxidation were globally upregulated. Changes to hepatic metabolism, together with the probable redirection of lipids to muscle thus spared the liver from lipid accumulation. Finally, in OR2 mice, lipid metabolism as a whole was downregulated, whereas thyroid hormone signaling was upregulated. The HFD response was also associated, in OP1 mice, with an upregulation of potassium channels and serotonin receptors, subsequently reversed in both OP2 and OR2 mice. Changes in DNA methylation were observed in the livers of OP1 mice and the muscle of OP2 mice. In the liver, <i>Set7/9</i> expression was decreased by the HFD in mice born to either lean or obese/diabetic mothers (F1LM and F2OM), whether OP or OR. In the livers of OP1 mice, DNA hypomethylation was associated with an upregulation of <i>Suv39h1</i> and <i>Suv39h2</i> expression, whereas, in both OR2 and OP2 mice, normal DNA methylation was associated with a decrease in <i>Jhdm2a</i> expression and an increase in the level of <i>Dnmt2</i> mRNA. In muscle, normal DNA methylation was associated with an upregulation of <i>Suv39h1, Set7/9</i> and <i>Dnmt2</i> in OP1 and OR2 mice, contrasting with the lower level of expression of the <i>Set7/9</i> and <i>Dnmt2</i> genes in the muscle of OP2 mice presenting DNA hypomethylation.</p

Analysis, by RT-qPCR, of the expression of genes encoding histone-modifying enzymes in the liver and muscle of mice fed the HFD, for both lean and obese mothers.

<p>The values shown are the ratios between OP1 or OR1 and CD1 and between OP2 or OR2 and CD2. They are expressed as the mean±SEM, <i>n</i> = 8 per group. ^a<i>p</i><0.05 for comparison with control CD, ^b<i>p</i><0.05 for comparison between OP and OR mice, ^c<i>p</i><0.05 for comparison between the F1LM and F2OM (maternal effect: lean versus obese mother), assessed by Kruskal-Wallis tests and <i>post hoc</i> Dunn’s tests.</p