Department of Evolution, Ecology, and Population Biology, Washington University in St. Louis, St. Louis, MO, 63105, USA.
Biology Department, 1032 W. Sheridan Road, Chicago, IL, 60660, USA.
BMC Genomics. 2018 Dec 7;19(1):888. doi: 10.1186/s12864-018-5327-0.
While the genetics of obesity has been well defined, the epigenetics of obesity is poorly understood. Here, we used a genome-wide approach to identify genes with differences in both DNA methylation and expression associated with a high-fat diet in mice.
We weaned genetically identical Small (SM/J) mice onto a high-fat or low-fat diet and measured their weights weekly, tested their glucose and insulin tolerance, assessed serum biomarkers, and weighed their organs at necropsy. We measured liver gene expression with RNA-seq (using 21 total libraries, each pooled with 2 mice of the same sex and diet) and DNA methylation with MRE-seq and MeDIP-seq (using 8 total libraries, each pooled with 4 mice of the same sex and diet). There were 4356 genes with expression differences associated with diet, with 184 genes exhibiting a sex-by-diet interaction. Dietary fat dysregulated several pathways, including those involved in cytokine-cytokine receptor interaction, chemokine signaling, and oxidative phosphorylation. Over 7000 genes had differentially methylated regions associated with diet, which occurred in regulatory regions more often than expected by chance. Only 5-10% of differentially methylated regions occurred in differentially expressed genes, however this was more often than expected by chance (p = 2.2 × 10).
Discovering the gene expression and methylation changes associated with a high-fat diet can help to identify new targets for epigenetic therapies and inform about the physiological changes in obesity. Here, we identified numerous genes with altered expression and methylation that are promising candidates for further study.
尽管肥胖的遗传学已经得到很好的定义，但肥胖的表观遗传学仍知之甚少。在这里，我们使用全基因组方法来鉴定与高脂肪饮食相关的 DNA 甲基化和表达存在差异的基因。
我们使遗传上相同的小型（SM/J）小鼠断奶，然后分别喂食高脂肪或低脂肪饮食，并每周测量它们的体重，测试它们的葡萄糖和胰岛素耐量，评估血清生物标志物，并在解剖时称重它们的器官。我们使用 RNA-seq（总共使用 21 个文库，每个文库由相同性别和饮食的 2 只小鼠混合而成）测量肝脏基因表达，使用 MRE-seq 和 MeDIP-seq（总共使用 8 个文库，每个文库由相同性别和饮食的 4 只小鼠混合而成）测量 DNA 甲基化。有 4356 个基因的表达与饮食有关，有 184 个基因表现出性别与饮食的相互作用。膳食脂肪失调了几个途径，包括细胞因子-细胞因子受体相互作用、趋化因子信号传导和氧化磷酸化途径。超过 7000 个基因的 DNA 甲基化区域与饮食有关，这些区域出现在调控区域的频率高于预期。然而，只有 5-10%的差异甲基化区域出现在差异表达的基因中，这比预期的更常见（p=2.2×10）。
发现与高脂肪饮食相关的基因表达和甲基化变化可以帮助识别新的表观遗传治疗靶点，并了解肥胖症中的生理变化。在这里，我们确定了许多表达和甲基化改变的基因，这些基因是进一步研究的有希望的候选基因。
