The genetics of variably-methylated transposable elements in inbred strains of mice

本博士项目的总体目标是研究母体肥胖对发育中的胚胎表观基因组和转录组的影响。母亲肥胖与后代的健康状况不佳有关，尽管这种情况发生的过程尚不清楚。我假设，与对照胚胎相比，暴露于母体高脂肪饮食的胚胎转录组和表观基因组（组蛋白修饰和/或甲基组）会发生显著变化。这些变化可能会持续到成年。为了探究这些问题，我将使用高脂肪饮食诱导的肥胖母鼠模型。第一批实验将集中在e6.5胚胎上，这些胚胎将通过自然定时交配产生，并将饮食暴露的雌性与维持饮食的雄性进行体外受精。收集到的胚胎将被解剖成胎盘和胚胎本身：从中生成ChIP- seq， BS-seq和RNA-seq文库，并分析来自低脂肪饮食和高脂肪饮食的母亲的胚胎之间的差异。在此之后，博士项目的目标可能会根据我得到的结果、我希望解决的生物学问题和各种技术的发展阶段而改变。我可能追求的一个方向将是确定在胚胎发育的哪个时间点出现这些表观遗传变化及其机制。另一个方向是在基因组调控的背景下描述这些表观遗传变化的功能含义和相关性。

Theme: Bioscience for HealthThe overall aim of this PhD project is to investigate the effect of maternal obesity on the epigenome and transcriptome of the developing embryo. Maternal obesity has been associated with poor health outcomes in offspring although the process by which this occurs is not well understood. I hypothesise that embryos exposed to a maternal high-fat diet will have significant changes to their transcriptome and epigenome (histone modifications and/or methylome) compared to control embryos. These changes may persist into adult life. To probe these questions, I will use a high-fat diet induced obese maternal mouse model. The first experiments will focus on e6.5 embryos which will be generated by natural timed matings as well as IVF of the diet-exposed females with chow-diet maintained males. The collected embryos will be dissected into the placenta and embryo proper: from these, ChIP- seq, BS-seq and RNA-seq libraries will be generated and analysed for differences between embryos derived from chow-diet exposed and high-fat diet exposed mothers. Following this, the aims of the PhD project may shift depending on the results I get, the biological question I wish to address and the stage of development of various technologies. One direction I may pursue will be establishing at what time point during embryonic development these epigenetic changes arise and the mechanism responsible. An alternative direction would be to characterise the functional implication and relevance of these epigenetic changes in the context of genomic regulation.