Mechanisms and functions of epigenetic reprogramming in the mammalian embryo

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Epigenetic marks such as DNA methylation and histone modifications are generally stable in somatic cells, but are reprogrammed on a genome wide scale in germ cells and early embryos. Approximately 80% of all the DNA methylation in the genome, for example, is erased in germ line cells (primordial germ cells). Reprogramming is important for imprinting, the return of the embryonic genome to pluripotency, the erasure of acquired epimutations, and probably also for the control of retrotransposons. Hence understanding reprogramming is crucial for insights into transgenerational epigenetic inheritance, the immortality of the germ line, and in order to harness the full potential of experimentally induced pluripotency (in iPS cells). Reprogramming epigenetic modifications may be useful to reverse some of the effects of ageing on somatic cells. You will join an interactive and collaborative team and will use cutting edge epigenomic profiling techniques based on high throughput sequencing and bioinformatics (in our in house epigenomics sequencing facility) in order to understand the dynamics of reprogramming on a genome wide scale together with discovering connections between epigenetic marks as well as with the transcriptome. Some of the candidate mechanisms for erasure of DNA methylation, which include modification of methylcytosine (eg by deamination or hydroxylation) coupled with base excision repair, are also being elucidated. You will be analyzing the expression of key candidate factors and use knockout mice and cell systems in which pathways that modify methylcytosine and those that are involved in DNA repair are mutated, in order to assess the effects in vivo on reprogramming and on lineage commitment in the early embryo. You may also use the iPS cell system in order to test the role in experimental reprogramming of selected epigenetic reprogramming factors.

Publications

10 25 50
 
Description We have developed a method to detect DNA damage which occurs very infrequently in the genome but is nonetheless critical to numerous biological processes, including immunity, DNA repair and development. Our data suggests that the presence of this damage in the genome is used to stimulate DNA repair which can lead to removal of epigenetic marks and therefore possibly loss of cell fate.
Exploitation Route We have developed the tools and more advanced hypotheses for this project, I think that this could be built upon by another researcher as another project.
Sectors Pharmaceuticals and Medical Biotechnology

 
Title uracil mass spec 
Description Development of a method to measure biological uracil levels using lcms/ms 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact Permitted the development of a sequencing method associated to the mass spec method; allows a deeper understanding of repair processes taking place in stem cells as a model for reprogramming systems 
 
Description uracil mass spec 
Organisation Babraham Institute
Country United Kingdom 
Sector Private 
PI Contribution Developed a mass spec method together
Collaborator Contribution Running of mass spec facility which we were able to use to run our samples, running our samples for us, discussions, method development
Impact Useable mass spec method, publication in preparation
Start Year 2014