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

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          Abstract

          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.

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          Most cited references 99

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          Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells.

          Cytosine methylation is required for mammalian development and is often perturbed in human cancer. To determine how this epigenetic modification is distributed in the genomes of primary and transformed cells, we used an immunocapturing approach followed by DNA microarray analysis to generate methylation profiles of all human chromosomes at 80-kb resolution and for a large set of CpG islands. In primary cells we identified broad genomic regions of differential methylation with higher levels in gene-rich neighborhoods. Female and male cells had indistinguishable profiles for autosomes but differences on the X chromosome. The inactive X chromosome (Xi) was hypermethylated at only a subset of gene-rich regions and, unexpectedly, overall hypomethylated relative to its active counterpart. The chromosomal methylation profile of transformed cells was similar to that of primary cells. Nevertheless, we detected large genomic segments with hypomethylation in the transformed cell residing in gene-poor areas. Furthermore, analysis of 6,000 CpG islands showed that only a small set of promoters was methylated differentially, suggesting that aberrant methylation of CpG island promoters in malignancy might be less frequent than previously hypothesized.
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            The metabolic syndrome.

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              The non-coding Air RNA is required for silencing autosomal imprinted genes.

              In genomic imprinting, one of the two parental alleles of an autosomal gene is silenced epigenetically by a cis-acting mechanism. A bidirectional silencer for a 400-kilobase region that contains three imprinted, maternally expressed protein-coding genes (Igf2r/Slc22a2/Slc22a3) has been shown by targeted deletion to be located in a sequence of 3.7 kilobases, which also contains the promoter for the imprinted, paternally expressed non-coding Air RNA. Expression of Air is correlated with repression of all three genes on the paternal allele; however, Air RNA overlaps just one of these genes in an antisense orientation. Here we show, by inserting a polyadenylation signal that truncates 96% of the RNA transcript, that Air RNA is required for silencing. The truncated Air allele maintains imprinted expression and methylation of the Air promoter, but shows complete loss of silencing of the Igf2r/Slc22a2/Slc22a3 gene cluster on the paternal chromosome. Our results indicate that non-coding RNAs have an active role in genomic imprinting.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                21 December 2010
                : 5
                : 12
                Affiliations
                [1 ]Inserm, AP-HP, Université Paris-Descartes, Faculté de Médecine, Hôpital Necker-Enfants Malades, U781, Paris, France
                [2 ]INRA, UMR1198, UMR INRA/ENV Maisons-Alfort/CNRS: Biologie du Développement et Reproduction, (ENV Maisons-Alfort; CNRS), Physiologie Animale et Systèmes d'Elevage, Centre de recherche de Jouy-en-Josas, Jouy-en-Josas, France
                [3 ]Laboratoire d'Epigénétique, CEA - Institut de Génomique, Centre National de Génotypage, Evry, France
                [4 ]Laboratory for Medical Epigenetics, Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
                [5 ]Unité Environnement Périnatal et Croissance, EA 4489, Université des Sciences et Technologies de Lille, Villeneuve d'Ascq, France
                [6 ]Laboratory of Cell Biology, Institute of Life Sciences, Catholic University of Louvain, Louvain-la-Neuve, Belgium
                [7 ]SBIM, Université Paris Descartes, Paris, France
                City of Hope National Medical Center, United States of America
                Author notes

                Conceived and designed the experiments: CGK AG JT JL BR CR DV TJE CJ. Performed the experiments: CGK AG JT MK SM EB MSG JT AV CB. Analyzed the data: CGK AG JT JL JPJ CJ. Contributed reagents/materials/analysis tools: JT JL CB BR CR DV. Wrote the paper: CGK AG CJ. Acquired funding for the experiments: JT JL BR CR DV TJE CJ. Supervised: CJ.

                Article
                10-PONE-RA-20534R2
                10.1371/journal.pone.0014398
                3006175
                21200436
                Gallou-Kabani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 13
                Categories
                Research Article
                Genetics and Genomics/Epigenetics
                Molecular Biology/DNA Methylation
                Diabetes and Endocrinology/Obesity
                Diabetes and Endocrinology/Type 2 Diabetes
                Nutrition/Obesity

                Uncategorized

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