The role of the KRAB zinc-finger protein ZFP57 in the maintenance of the methylation programme in mouse development

Lead Research Organisation: University of Cambridge
Department Name: Physiology Development and Neuroscience


DNA is packaged inside our cells into bundles called chromosomes. Chromosome packaging is a highly regulated process that ensures that the correct cell makes the correct genes available for proper regulation specific to that cell. We are interested in the factors that regulate DNA packaging into chromosomes and in particular we are interested in the changes that happen to chromosome packaging as stem cells develop into body cells. We have made a mutant where key factors required for proper gene regulation are not placed on the DNA and the chromosomes. These experiments are designed to learn more about this key factor and how it influences the chromosomes in early development.

Technical Summary

In mammalian preimplantation embryos, DNA methylation patterns are lost and subsequently reaquired by de novo methylation. This epigenetic reprogramming is believed to be important for the regulation of pluripotency genes. In contrast, genomic methylation imprints, heritable methylation states acquired in the germline and required for the correct mono-allelic expression of imprinted genes after fertilisation, are resistant to epigenetic reprogramming. This resistance to reprogramming ensures that the epigenetic memory which differentially marks the maternal and paternally inherited chromosomes at imprinted loci, remains heritable in embryos. It is not understood what makes methylation imprints resistant to epigenetic reprogramming. We have recently identified a KRAB zinc-finger protein, ZFP57, that when absent from both the egg and the zygote, results in loss of methylation from germline imprints. This suggests an important role for this factor in the maintenance of genomic imprints in preimplantation embryos. Here we propose a series of experiments to: 1. Identify the extent to which imprints are regulated by ZFP57. 2. Identify genomic target sites for ZFP57. 3. Determine the relationship between the KRAB-binding co-repressor KAP1 and imprinting control. 4. Identify ZFP57 interacting partners, including DNA methyltransferases. Using these approaches we aim to test the hypothesis that ZFP57 maintains methylation by specifically targeting the DNA methyltransferase machinery to germline imprints, and to better understand the newly defined role for KRAB-zinc-finger proteins in the in vivo regulation of the mammalian epigenetic programme.


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Description We have identified and published target sites for ZFP57 identifying imprinted and non-imprinted unique targets as well as 2000 endogenous retroviruses of the IAP class.
In addition to parental origin specific targets (imprinting control regions) in hybrids, we have identified genetic background specific targets in which the target sequence contains a strain-specific polymorphism hence abrogating binding. Functional correlates of ZFP57 binding were therefore assessed indicating a role for this protein in the regulation of these genes.
We have generated mutant mice for ZFP57 and mutant ES cells from both maternal-zygotic and zygotic mutants. We have been able to assess the outcome of these mutations with zygotic mutants showing a partially penetrant embryonic lethality and the maternal-zygotics, a fully penetrant lethality. The zygotic mutation recapitulates the defects observed in human patients with a multi-locus imprinted disorder. Aspects of this work have now been published.

In addition, in work not outlined in the grant, we have collaborated on a study to investigate the role of KAP1/TRIM28, a cofactor involved in the targeting of repressive epigenetic modifications to specific sites including imprints, on the genome. This work was recently published in Cell.
Exploitation Route Yes - we are continuing to study the mechanisms underlying targeting of epigenetic states using this and related mutant mouse lines.
Sectors Environment,Other

Description Wellcome Trust Senior Investigator Award
Amount £2,008,652 (GBP)
Funding ID WT095606RR 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2011 
End 11/2018