Le transcriptome et le méthylome du foie des rats dénutris en période périnatale identifient les gènes principaux impliqués dans les pathologies métaboliques

Abstract : One of the most striking features of metabolic programming is that a common physiopathological output at adulthood is obtained irrespective to the nutritional insult during early life. This has suggested that the metabolic alterations due to early nutritional stress might result from the programming of only a small number of genes which act as gatekeepers of a fundamental gene network or signalling pathway. Here we aimed to test this hypothesis through the combined analysis of the transcriptome and methylome in rat liver samples derived from animals born to dams fed either a protein-restricted diet (MPR) or a methyl donor deficient (MDD) diet through gestation and lactation. At weaning, the offspring born to MDD dams were sacrificed whereas the pups from the MPR group were fed standard chow until the age of 6 months. 21-day-old rats born to mothers fed a MDD diet during gestation and lactation have 3,269 over-expressed (P<0.0009) and 2,841 under-expressed (P<0.0004) genes compared to controls. Modifications of DNA methylation were found in the promoter regions of 1,032 genes. Functional analyses revealed that these genes are mainly involved in glucose and lipid metabolism, nervous system, coagulation, endoplasmic reticulum stress and mitochondrial function. Master genes exhibiting changes in both gene expression and DNA methylation are limited to 266 genes and are mainly involved in the renin-angiotensin system, mitochondrion metabolism and phospholipid homeostasis. Most of these master genes participate in Non Alcoholic Fatty Liver Disease (NAFLD). Maternal protein restriction (MPR) resulted in increased fat mass, hypertriglyceridemia, hypercholesterolemia and high fatty acids compared to control. 3,020 genes were up-regulated (p < 0.0003) and 3,601 (p ? 0.002) down-regulated by MPR compared to controls. Modifications of DNA methylation was found in 3,968 genes. The functional analysis indicated that the overexpressed genes were mainly involved in metabolic pathways and the under-expressed and differentially methylated genes were mainly involved in physiological process. 998 master genes were found, functional analysis of these genes indicated a significant effect on tissue development, regulation of transcription and metabolism, and many of them are associated with chronic diseases such as hypertension, central obesity and diabetes. The genome-wide expression and DNA metylation results obtained using these models, were compared to previous methylome and transcriptome data obtained using liver from MPR pups sacrificed at birth. This analysis revealed a common set of 46 genes that were up regulated and 42 genes down regulated in the three models of metabolic programming compared to control animals. Most of the up regulated genes are involved in the regulation of mitochondrial function whereas the down-regulated genes are mainly involved in the regulation of cell proliferation and gene expression. We identified also a set of 122 genes whose methylation levels were changed both by methyl donor deficiency and protein-restriction. These observations sustain the hypothesis that a small set of core genes underlies the programming of metabolic disorders irrespective of the nutritional insult
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Gaili Chen. Le transcriptome et le méthylome du foie des rats dénutris en période périnatale identifient les gènes principaux impliqués dans les pathologies métaboliques. Biochimie, Biologie Moléculaire. Université de Lorraine, 2014. Français. ⟨NNT : 2014LORR0152⟩. ⟨tel-01751040⟩

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