Inserm, AP-HP, Université Paris-Descartes, Faculté de Médecine, Hôpital Necker-Enfants Malades, U781, Paris, France.
PLoS One. 2010 Dec 21;5(12):e14398. doi: 10.1371/journal.pone.0014398.
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.
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.
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.
胎盘印迹基因剂量的变化可能会影响产前对营养资源的控制。事实上，单等位基因的行为和对区域表观遗传状态变化的敏感性，使印迹基因既脆弱又具有适应性。
我们研究了妊娠期间高脂肪饮食（HFD）是否会改变胎盘印迹基因的表达以及局部和全基因组 DNA 甲基化模式。在妊娠的前 15 天，怀孕的老鼠分别喂食 HFD 或对照饮食（CD）。我们通过 RT-qPCR 分析 20 个印迹基因，比较了总胎盘匀浆中雄性和雌性后代的基因表达模式。在染色体 6、7、12 和 17 上的四个簇中，有九个基因表现出性别二态性和对饮食的敏感性。通过原位杂交检测，这些变化不是由于胎盘各层比例的变化引起的。对染色体 17 簇差异甲基化区域（DMR）内 30 个 CpG 的亚硫酸氢盐测序分析显示，在两个明显的亚区内，个体 CpG 存在性别和饮食特异性的差异甲基化。生物信息学分析表明，这些差异甲基化的 CpG 可能位于转录因子或参与染色质重塑的因子的识别元件或结合位点内。通过 LUMA 技术评估的胎盘全基因组 DNA 甲基化在 CD 上也存在性别二态性，雄性胎盘的甲基化水平低于雌性胎盘。HFD 仅导致雌性胎盘的全基因组 DNA 低甲基化。亚硫酸氢盐焦磷酸测序显示，B1 或 LINE 重复元件都不能解释这些 DNA 甲基化差异。
妊娠期间的 HFD 会在 CpG 内以及整个基因组中引发性别特异性的表观遗传改变，同时还会导致控制许多细胞、代谢和生理功能的印迹基因簇的失调，这些功能可能与适应和/或进化有关。这些发现强调了在流行病学方案和饮食干预中研究两性的重要性。
