Mechanisms targeting epigenetic states in mammals

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Our group is interested in mammalian development and in particular in how genes are regulated. We focus on epigenetic mechanisms, which are about how our genes are packaged along the chromosome, to make them able to be turned on or off. In human, almost half of the genome is composed of bits of DNA that are repeated over and over again. They do not resemble the protein coding genes that are important for our cells. However, these repetitive elements have the ability to "jump" and integrate themselves all over the genome with the potential to disrupt the proper regulation of our genes. A large family of proteins, the KRAB zinc finger proteins (KZFP), have evolved to be able to silence these mobile repetitive elements by targeting repressive epigenetic states to these repeats. Thus, KZFPs are thought to have evolved in parallel with mobile repetitive elements to repress their activity.Interestingly, one KZFP that we have been studying has been shown to target unique regions of the genome, and not just repeat elements. This has completely changed our understanding of this family, as it suggests that these proteins evolved to have more specialised functions regulating protein-coding genes. In a preliminary study, we have identified another KZFP that also targets unique regions. It is an ancient protein highly conserved in mammals, meaning that it must have been preserved during evolution and so is very likely to have an essential role in mammals. It is also expressed throughout mouse development and in most human tissues. We identified its target genes in mouse cells, and found that this is a very unusual KZFP. It seems to act in a different way than most others, and does not seem to be able to recruit the same co-factor as the others. It appears that this is not a silencing KZFP but one that does the opposite and contributes to gene activation. Because this KZFP is so unusual and so highly conserved in mammals, we propose to investigate its functions further using mice models. We have generated mice that are mutant for the gene encoding this KZFP and hence are depleted of the protein. We will follow their development and assess what is wrong with them and impact of the mutation on their life-course. This will tell us what this protein is doing and why it has evolved its unusual properties. We will aim at understanding the action of this protein by identifying its molecular partners and the role of different parts of it.Overall, this project will not only help us to characterize an important protein in mammals but also it will help us to gain greater insight into the evolution and function of this large family of KZFP. We believe we will learn more about how these proteins behave on the molecular level and will better understand how epigenetic mechanisms are targeted to specific unique regions of the genome.