University of Edinburgh
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BBSRC EASTBIO R(D)SVS PhD
Genomic features recruiting repressive polycomb group (PcG) complexes during evolution and development
Supervisors: Doug Vernimmen, David E.K. Ferrier
Polycomb group (PcG) complexes are widely used to control gene expression, but there are intriguing differences in their modes of operation in different species, which is poorly understood. 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 were first identified in Drosophila melanogaster. PcG in Drosophila are recruited to specific sequences called polycomb repressive elements, whereas in mammals these complexes are recruited by CGIs (1,2).
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 a-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.
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.
The student will use available reference genomes to analyse the number of CGIs at transcriptional start sites (TSS) per genome and rank according to CpG density. This will be compared according to number of genes and genome size. CGI vs non-CGI TSS will be analysed and orthologous genes compared. Training in bioinformatics will be given, with many pipelines already developed in-house (Deen et al., submitted). Modular training courses are also available internally and via Edinburgh Genomics. Roslin also hosts numerous bioinformaticians who can provide the necessary expertise and training. During the first two years, the student will characterise CGIs across a variety of mammalian species, then expanding from birds across to invertebrates. We will take advantage of the FAANG databases to access the transcriptional profiles of these species. During the third year, the student will undertake experimental work, using ChIP-seq PcG mark (H3K27me3) and its association with repressed genes to validate the functionality of CGIs in the species studied. The fourth year will focus on data collation and publication.
This study will provide an unprecedented evolutionary model of gene regulation across species.
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