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

我们对了解印记表达的机制很感兴趣。是什么让一个印记基因在一对染色体中的一条而不是两条染色体上表达？这个过程导致只有父系遗传或母系遗传的拷贝被表达，是一个“表观遗传”。表观遗传学意味着“遗传学之上”，印记基因的表观遗传状态表现为仅位于一条亲本染色体上的DNA上的化学修饰，而不是另一条染色体，导致位于那里的基因在其中一条染色体上表达，并在另一条染色体上保持。我们的目标是产生新的知识，了解两个亲本染色体在一个印记域上的样子，以及这如何影响一个亲本拷贝的开启和另一个的关闭。在我们的第一个目标中，我们将比较遗传自父亲的染色体与遗传自母亲的染色体，在印记域。这将使我们能够确定两个父母遗传的染色体是否彼此不同地包装，反过来，这是否是正在研究的结构域中基因表达或抑制的原因或结果。在我们的第二个目标中，我们研究了一个非常重要的印记基因，主要存在于大脑中，试图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胚胎能够“修复”丢失的DNA甲基化。这种对甲基化损失的恢复力对后代的健康和福祉有影响。在我们的第三个目标中，我们将研究甲基化可以恢复的序列和进行恢复的机制。特别是，使用小鼠作为模型，我们将研究这一过程是否在肥胖母亲或老年母亲中受到损害，导致其后代异常甲基化，影响其终身健康。

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.