A single fertilised mouse egg carries two chemically distinct copies of the same gene—one from the mother, one from the father—and this project will try to build those chemical marks from scratch. The work addresses a fundamental gap in evolutionary biology: why some mammals, but not others, use a system called genomic imprinting to silence one parental copy of certain genes. In humans, errors in this process cause rare developmental disorders, but the rules that govern which genes become imprinted, and how new imprinted regions arise over evolutionary time, are unknown. The researcher plans to artificially switch on normally silent genes in mouse egg cells, then track whether the resulting DNA methylation patterns persist after fertilisation. If successful, this would show that new imprinted regions can be created by simply changing which genes are active—a direct test of a long-standing hypothesis. This is fundamental science. It will not produce a medical treatment or diagnostic test in the near term. But understanding how imprinting evolves could eventually explain why the system exists at all, and why it is confined to marsupials and placental mammals. Similar curiosity-driven work on epigenetic marks in the past has reshaped how we understand inheritance, development, and even the origins of certain cancers.
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Genomic imprinting, a complex and essential epigenetic phenomenon in mammals, regulates gene expression in a parent-of-origin specific manner. The majority of imprinted genes are regulated by differentially methylated regions (DMRs), wherein DNA methylation is differently marked between the paternal and maternal alleles. Intriguingly, while the number of maternally imprinted DMRs varies among different mammalian groups, the molecular mechanisms underlying the acquisition of such novel lineage-specific imprinted DMRs remain elusive. This project aims to advance our understanding of the interplay between pre-existing genetic context (i.e. protein binding motifs) and new genetic changes (i.e. novel transcription) in the process of acquiring imprinted DMRs in the mammalian genome. To address this, the prime objective of this project is to establish novel DNA methylation domains, by inducing expression of otherwise repressed genes in oocytes, and characterise the epigenetic status of novel methylated regions after fertilisation. My research has the potential, not only to advance our understanding of the evolutionary mechanisms of genomic imprinting, but also to provide clues to address why such a phenomenon exists, and has evolved, only in marsupial and eutherian mammals. By transferring the expertise of the host lab, which has pioneered the model of transcription-dependent establishment of DNA methylation in mammalian oocytes, this project will also support me in establishing myself as a leading independent researcher in the field of epigenetics.
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