Genomic imprinting and the epigenetic control of genome function: regulation, redundancy and resilience

基因组印记和基因组功能的表观遗传控制：调节、冗余和恢复力

• 批准号: MR/X018407/1
• 负责人: Anne Ferguson-Smith
• 金额: $ 351.13万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018407%2F1
• 关键词: Genomic; imprinting; epigenetic; control; genome

We are interested in understanding mechanisms of imprinted expression. What makes an imprinted gene be expressed from one of the chromosomes in a pair rather than both of them? The process causing only the paternally inherited or the maternally inherited copy to be expressed, is an 'epigenetic' one. Epigenetics means 'on top of genetics' and the epigenetic state at an imprinted gene is manifested as chemical modifications that sit on the DNA at only one parental chromosome and not the other causing the gene located there to be expressed on one of the chromosomes and kept off on the other. Our goal is to generate new knowledge about what the two parental chromosomes look like at an imprinted domain and how that influences one parental copy being on and the other being off. In our first aim we will compare the chromosome inherited from dad, with the chromosome inherited from mum, at an imprinted domain. This will allow us to identify if the two parentally inherited chromosomes are packaged differently from each other and in turn, whether this is a cause or a consequence of the expression or repression of the genes in the domain being investigated. In our second aim, we study a very important imprinted gene predominantly in the brain, to try and understand more about human diseases that are associated with abnormalities in this gene. Finally, we have recently discovered that the preimplantation embryo is able to 'repair' lost DNA methylation. This resilience to methylation loss has implications for offspring health and well being. In our third aim, we will characterise the sequences where methylation can be restored and the machinery that does the restoration. In particular, using the mouse as a model, we will investigate whether this process is compromised in obese mothers or aged mothers leading to abnormal methylomes in their offspring with implications for their life long health.

我们有兴趣了解印迹表达的机制。是什么使一个烙印基因从一对染色体中而不是两个染色体表达？仅引起父亲遗传或母体继承的副本的过程是“表观遗传”。表观遗传学的意思是“在遗传学之上”，而表观遗传学状态在一个烙印基因上表示为化学修饰，仅在DNA上仅位于一种父母染色体上，而不是另一个导致该基因的基因在其中一种染色体上表达的基因，而另一种则保持不变。我们的目标是产生有关两个父母染色体在一个烙印领域的外观以及它如何影响一个父母副本以及另一个正在熄灭的知识。在我们的第一个目标中，我们将比较从父亲那里继承的染色体，并在一个烙印的领域中从妈妈那里继承的染色体。这将使我们能够识别两个父遗传的染色体是否彼此包装不同，而这反过来，这是原因或抑制所研究域中基因表达或抑制的原因还是结果。在我们的第二个目标中，我们主要在大脑中研究一个非常重要的印迹基因，并尝试更多地了解与该基因异常相关的人类疾病。最后，我们最近发现，植入前的胚胎能够“修复”失去的DNA甲基化。这种对甲基化损失的韧性对后代健康和福祉具有影响。在我们的第三个目标中，我们将表征可以恢复甲基化的序列以及进行修复的机械。特别是，使用小鼠作为模型，我们将研究该过程是否在肥胖的母亲或老年母亲中损害，导致其后代异常的甲基瘤，对他们的寿命长期健康。

项目成果

Epigenetic control and genomic imprinting dynamics of the Dlk1-Dio3 domain.

• DOI: 10.3389/fcell.2023.1328806
• 发表时间: 2023
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5