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

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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.