Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605, USA.
Sci Rep. 2017 Mar 14;7(1):174. doi: 10.1038/s41598-017-00267-9.
Diet plays a crucial role in shaping human health and disease. Diets promoting obesity and insulin resistance can lead to severe metabolic diseases, while calorie-restricted (CR) diets can improve health and extend lifespan. In this work, we fed mice either a chow diet (CD), a 16 week high-fat diet (HFD), or a CR diet to compare and contrast the effects of these diets on mouse liver biology. We collected transcriptomic and epigenomic datasets from these mice using RNA-Seq and DNase-Seq. We found that both CR and HFD induce extensive transcriptional changes, in some cases altering the same genes in the same direction. We used our epigenomic data to infer transcriptional regulatory proteins bound near these genes that likely influence their expression levels. In particular, we found evidence for critical roles played by PPARα and RXRα. We used ChIP-Seq to profile the binding locations for these factors in HFD and CR livers. We found extensive binding of PPARα near genes involved in glycolysis/gluconeogenesis and uncovered a role for this factor in regulating anaerobic glycolysis. Overall, we generated extensive transcriptional and epigenomic datasets from livers of mice fed these diets and uncovered new functions and gene targets for PPARα.
饮食在塑造人类健康和疾病方面起着至关重要的作用。促进肥胖和胰岛素抵抗的饮食会导致严重的代谢疾病，而热量限制（CR）饮食可以改善健康并延长寿命。在这项工作中，我们用标准饮食（CD）、16 周高脂肪饮食（HFD）或 CR 饮食喂养小鼠，以比较和对比这些饮食对小鼠肝脏生物学的影响。我们使用 RNA-Seq 和 DNase-Seq 从这些小鼠中收集转录组和表观基因组数据集。我们发现 CR 和 HFD 都诱导了广泛的转录变化，在某些情况下，以相同的方向改变相同的基因。我们使用我们的表观基因组数据来推断附近这些基因的转录调节蛋白，这些蛋白可能影响它们的表达水平。特别是，我们发现了 PPARα 和 RXRα 发挥关键作用的证据。我们使用 ChIP-Seq 来分析 HFD 和 CR 肝脏中这些因子的结合位置。我们发现了大量参与糖酵解/糖异生的基因附近的 PPARα 结合，揭示了该因子在调节厌氧糖酵解中的作用。总的来说，我们从这些饮食喂养的小鼠肝脏中生成了广泛的转录组和表观基因组数据集，并发现了 PPARα 的新功能和基因靶点。
