Abstract
BackgroundChanges 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 FindingsWe 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.ConclusionsA 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.
Highlights
There is no doubt that much of the increase in obesity can be attributed to lifestyle factors, such as the excess consumption of energy-rich foods, a decline in physical activity, inherited genetic and other factors [1]
A high-fat diet (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
HFD-fed mothers had a weight gain that was higher than control diet (CD) fed mothers (14.060.3g vs 10.360.3g, p = 0.0001), but when the weight gain is reported in relation to the number of fœtuses, there was no difference in weight gain between animals on the two different diets (2.060.13g vs 1.860.13g, p = 0.2173)
Summary
There is no doubt that much of the increase in obesity can be attributed to lifestyle factors, such as the excess consumption of energy-rich foods, a decline in physical activity, inherited genetic and other factors [1]. Little is known about the potentially deleterious effects of overnutrition, such as a typical hypercaloric Western diet rich in energy, saturated fats and sugar or a high-fat diet, on the health of offspring, potentially resulting in a metabolic syndrome phenotype in the offspring [3,4,5]. Changes in imprinted gene dosage in the placenta may compromise the prenatal control of nutritional resources. Monoallelic behaviour and sensitivity to changes in regional epigenetic state render imprinted genes both vulnerable and adaptable
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