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An evolutionary approach to understanding gene regulation by the Polycomb group complexes


College of Medicine and Veterinary Medicine

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Dr Douglas VERNIMMEN , Dr J Smith , Dr D E K Ferrier No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Rationale: In vertebrate genomes, CpG dinucleotides are relatively depleted, except in specific regions showing high density. These regions are known as CpG islands (CGIs) and consist of short (~ 1kb) interspersed CpG-rich, predominantly un-methylated DNA sequences, associated with a transcriptionally-permissive chromatin state. Interestingly, the human genome harbours 2x more annotated CGIs than the mouse. The functional significance of these CGIs for correct regulation of developmentally-regulated genes is still poorly understood. CGIs were originally identified in promoters of housekeeping genes and associated with H3K4me3 independent of gene activity. CGIs have now also been found in around half the promoters of developmentally-regulated/tissue-specific genes. In these CGIs, repressive polycomb group (PcG) complexes block transcription in inappropriate lineages or at non-expressing differentiation stages. PcGs involved in the deposition of histone marks associated with transcriptional repression (H3K27me3) were first identified in Drosophila melanogaster. PcG in Drosophila are recruited to specific sequences called polycomb repressive elements (PRE), whereas in mammals these complexes are recruited by CGIs (1,2).

Hypothesis: It was originally hypothesised that CGIs at developmentally-regulated genes may be relics of ancestral CGIs differentially maintained during evolution (3). However, only the well-studied α-globin locus has provided a good example supporting this hypothesis: the human α-globin genes are associated with a CGI which appears to have been lost in rodents during evolution (2). The presence of a CGI in human therefore has an important implication for the epigenetic regulation of this locus. Comprehensive genomic studies spanning a broad variety of species are therefore needed to validate this hypothesis.

Aim: To study the genomic sequences recruiting PcG across species and investigate their role in epigenetic regulation of their target genes. The availability of numerous reference genomes will enable the study of these sequences across major taxa. This study will provide an unprecedented evolutionary model of gene regulation across species.  

Funding Notes

3.5 year PhD

This opportunity is open to UK and international students and provides funding to cover stipend, tuition fees and consumable/travel costs. Applications including a statement of interest and full CV with names and addresses (including email addresses) of two academic referees, should be emailed to [Email Address Removed].

When applying for the studentship please state clearly the project title/s and the supervisor/s in your covering letter.

Other projects available:
We would encourage applicants to list up to three projects of interest (ranked 1st, 2nd and 3rd choice) from those listed with a closing date of 10th January 2021 at https://www.ed.ac.uk/roslin/work-study/postgraduate/studentships

References

1. Mendenhall, E.M., Koche, R.P., Truong, T., Zhou, V.W., Issac, B., Chi, A.S., Ku, M. and Bernstein, B.E. (2010) GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet, 6, e1001244.
2. Lynch, M.D., Smith, A.J., De Gobbi, M., Flenley, M., Hughes, J.R., Vernimmen, D., Ayyub, H., Sharpe, J.A., Sloane-Stanley, J.A., Sutherland, L. et al. (2012) An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J.
3. Antequera, F. (2003) Structure, function and evolution of CpG island promoters. Cellular and molecular life sciences : CMLS, 60, 1647-1658.
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