MRC DTG studentship: Role of transcriptional events in establishment of imprinted methylation

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

We inherit a set of genes from our mother and our father. For most genes, both copies are equally active, irrespective of parentage. A few genes defy this rule, one copy being silenced by a process that begins in the germ cells - the cells that will combine to form the embryo at fertilisation - and these are called imprinted genes. Imprinted genes have particularly important roles in how the fetus grows and develops. We are investigating how imprinted genes are marked in this way in the egg cell. It is important that these marks are laid down correctly. Mistakes in this process that could occur because of environmental factors or through procedures like assisted reproduction technologies may not be corrected in the fetus and may lead to developmental abnormalities or an increased risk of disease in later life.

Publications

10 25 50
 
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. Based on our previous work that identified an important and potentially universal mechanism in how imprinted genes are marked in gametes, this project has looked systematically at the association between transcription and DNA methylation at imprinted control regions in mouse gametes. It has established the general principle that imprinting control regions in oocytes are CpG islands associated with inactive promoters but located within active transcription units. Moreover, it has revealed that there is a substantial change in promoter use between fetal germ cells and postnatal growing oocytes (in which acquisition of DNA methylation initiates), which has the effect of placing many CpG islands destined for methylation within active transcription units. Finally, by comparison with male germ cells, it provides some explanation for the gender-specificity of genomic imprinting.
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