Role of germline transcription events in DNA methylation acquisition at imprinted genes

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

We inherit genes from our fathers and mothers and for most of our genes the copies we receive from either parent are equally active. An important exception to this general rule occurs in a process called genomic imprinting, whereby one gene copy is deliberately silenced. These imprinted genes are important in determining how the fetus grows and how infants adapt their physiology to life outside the womb. But the fact that these genes have one copy that is preselected to being silent poses a risk and makes them particularly vulnerable to mutation events, such as occurs in cancer. Imprinted genes behave in this manner because they are marked in different ways in the male and female germ cells (sperm and eggs). How these genes are so marked is not fully known, and it is important to find out, because if the marking process goes wrong problems in fertility or developmental abnormalities may arise. By analysing a single imprinted gene in some detail, we have discovered an important part of the mechanism in the germ cell marking event. In this research, we wish to understand this mechanism in more detail and we need to show that it could apply generally to imprinted genes. This work will be done in a model system, but it will provide important new insights for human studies.

Publications

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Kelsey G (2011) DNA methylation: a new twist in the tail. in Cell research

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Kelsey G (2013) New insights into establishment and maintenance of DNA methylation imprints in mammals. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Smallwood SA (2012) De novo DNA methylation: a germ cell perspective. in Trends in genetics : TIG

 
Description Genomic imprinting is an important epigenetic mechanism in mammals that results in monoallelic silencing of a subset of our genes in a strict parent-of-origin manner. A key point in imprinting is how these special genes are marked in the gametes: the sperm and egg. This project has extended our earlier findings that transcription is required to epigenetically mark imprinted genes in gametes. Based on this model, we have generated a knock-out at a second imprinted locus and demonstrated that preventing transcription through the imprinting control region does prevent acquisition of DNA methylation in oocytes. In this project, we have also widened the analysis to ask whether a requirement for transcription exists generally for CpG island that might become methylated in mouse oocytes. By adapting a bisulphite sequencing technique to work with very low numbers of cells, we identified ~1000 CpG islands highly methylated in mouse oocytes. We demonstrated a predominant intragenic location of these methylated CpG islands and a relative deficiency of a key histone modification, H3K4me3. Surprisingly, we also found that prior methylation in gametes was the major factor in whether a CpG island is methylated in blastocysts.
Exploitation Route Knowledge of how techniques associated with assisted reproduction techniques could lead to alteration in epigenetic marking of genes would be important in further optimising methods use for handling eggs and sperm and culturing embryos before implantation or in storage and recovery or frozen and stored embryos. There are implications for our findings, for example, in epigenetic defects that might arise in association with assisted reproduction techniques. This possibility would require further work to substantiate before relevant stakeholders were engaged.
Sectors Healthcare

 
Description The demonstration that gene transcription confers DNA methylation during female gametogenesis has started to inform studies that evaluate the safety of procedures associated with assisted reproduction, leading to collaborations with translational implications; for example PMID: 31856890
First Year Of Impact 2019
Sector Healthcare
 
Description Antisense-mediated promoter silencing in imprinted locus Gnas 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Our team provided a gene targeting construct for one of the targeting alleles used by the partner, which complemented work we previously published in Chotalia et al. 2009 Genes & Dev.
Collaborator Contribution Their team was responsible for framing the project and experimental design and data analysis.
Impact Joint publications Williamson et al. PLoS Genet. 2011; Tibbit et al., 2015 Non-coding RNA
Start Year 2007