Determining the lasting impact on the developing epigenome by gestational toxic exposures

确定妊娠期有毒物暴露对发育中的表观基因组的持久影响

• 批准号: MC_UU_00025/9
• 负责人: Mathew Van De Pette
• 金额: $ 219.29万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Intramural
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_UU_00025%2F9
• 关键词: Determining; lasting; impact; developing; epigenome

Geno-toxicity, whereby a toxic compound causes changes to the genetic code through mutation, has received widespread attention from the research community. Effects of toxic insults on the epigenome, where the genetic code is not directly affected, instead the ability to correctly read this code, remain poorly understood. The programme focusses on developing our understanding of the action and mechanism of chronic sub-toxic insults on the epigenome. These occur when a substances dose is insufficient to cause acute toxicity, but instead alters the environment of the DNA. The programme will have a particular emphasis on the lasting impact of these exposures during pregnancy. These toxic events can be environmental or pharmaceutical, and we aim to identify similarities and differences in such diverse challenges. We employ standard genomics and molecular biology techniques, in addition to using a new approach to studying epigenetics. We have generated a series of transgenic mouse lines, which can “see” the epigenetic status of a gene, through imaging of a mouse in vivo. Using these approaches, we can track epigenetic change through life-course and across generations, thereby “seeing” the toxic insult in its entirety.

遗传毒性是一种有毒化合物通过突变导致遗传密码改变的现象，已受到研究界的广泛关注。有毒侮辱对表观基因组的影响仍然知之甚少，表观基因组中的遗传密码不会直接受到影响，而是正确阅读该密码的能力。该计划的重点是发展我们对慢性亚毒性侮辱对表观基因组的作用和机制的理解。当一种物质的剂量不足以引起急性毒性时，就会发生这种情况，但会改变DNA的环境。该方案将特别强调孕期接触这些物质的持久影响。这些有毒事件可能是环境方面的，也可能是药品方面的，我们的目标是找出这些不同挑战中的相似和不同之处。除了使用一种新的方法来研究表观遗传学外，我们还使用了标准的基因组学和分子生物学技术。我们已经产生了一系列转基因小鼠品系，通过对小鼠体内的成像，这些转基因小鼠可以“看到”基因的表观遗传状态。使用这些方法，我们可以追踪表观遗传学在整个生命过程和世代之间的变化，从而“看到”有毒侮辱的全部。