Epigenetic mechanisms maintain the heritable characteristics of cells and functional differences between cell types, without changes to the DNA sequence. Epigenetic changes influence gene regulation together with transcription factors in response to signalling. DNA methylation is a repressive epigenetic modification involving the covalent addition of a methyl group to cytosine by DNA methyltransferases. The relationship between DNA methylation and gene silencing is indirect for many genes, via the function of histone modifying complexes and the formation of condensed chromatin. DNA methylation and other epigenetic marks are essential for mouse development after gastrulation stage, implying that they are required when differentiation occurs and gene expression patterns are propagated through cell lineages. In vitro cultured mouse embryonic stem cells (mESCs) can self-renew without these epigenetic marks but are impaired for differentiation to most cell fates. It is still not well understood why repressive epigenetic pathways are necessary for development and in the transition from stem cells to differentiated cells.
To address these research questions, we will use mESC model systems, in which global DNA methylation levels can be controlled and cell stress can be measured. Colour markers in the cells will be used to report on methylation and differentiation status, or cell stress status. The first aim is to determine the threshold of DNA hypomethylation necessary for differentiation. We will assess how this affects the generation of cell types in embryoid body /gastruloid differentiation models, and organoid synthetic biology assemblies, based on gene expression changes. Conversely, we aim to determine the effects of controlled DNA methylation loss on somatic cells derived from these mESCs, to determine the methylation threshold for hypomethylated somatic cells that is necessary to retain their identity. We will determine factors involved in this process and compare the requirements of different cell types, including neuronal, heart and liver cells, of which our labs have expertise, based on gene expression changes in cultured embryos, and in vitro models for embryonic gastrulation and somatic cell organoids.
This project will contribute novel insights into ‘the rules of life’ that will contribute understanding of health and ageing by asking a fundamental question of how our cells function in the absence of epigenetic mechanisms, to determine how cells rely on these pathways. Previous work suggests that the integrity of epigenetic mechanisms is linked with healthy ageing and understanding its precise role may identify possible new targets for regenerative therapy of chronic and degenerative conditions.
Funding information and application procedures:
This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP) http://www.eastscotbiodtp.ac.uk/how-apply-0 .
This opportunity is open to UK and international students and provides funding to cover stipend and UK level tuition fees. The University of Edinburgh will cover the difference between home and international fees meaning that the EASTBIO DTP will offer fully-funded studentships to all appointees. However there is a cap on the number of international students the DTP can recruit. It is therefore important for us to know from the outset which fees status category applicants will fall under when formally applying for entry to our university.
Please refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.
EASTBIO Application and Reference Forms can be downloaded via http://www.eastscotbiodtp.ac.uk/how-apply-0
Please send your completed EASTBIO Application Form along with a copy of your academic transcripts to [Email Address Removed]
You should also ensure that two references have been sent by the deadline using the EASTBIO Reference Form.’’