Epigenetic control of seasonal timing

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We will investigate how seasonal clocks timing reproduction and metabolism are regulated by epigenetic processes. This arises from our discovery that melatonin - the seasonal timer hormone - controls dynamic changes in gene methylation state in the pars tuberalis (PT) of the pituitary gland, and may activate or suppress multiple pathways in rhythmic manner each day.

We will measure using high resolution bi-sulphite sequencing how genome-wide changes in methylation change in different photoperiods, defining modifications to specific CpG sites. In parallel we will use genome-wide RNA sequencing (RNA-Seq) to study expression of coding and non-coding genes, to develop predictive models of gene expression, including transcriptional (TF/TFBS's), post-transcriptional (microRNAs/target genes) and epigenetic (e.g. methylation/demethylation, histone modifications). These studies will be undertaken in both the PT and hypothalamus, where thyroid hormone metabolism is regulated by output from the PT. Long-term seasonal physiological responses may be regulated by gradual epigenetic changes, mapped as methylome changes in photorefractory animals. We will test the hypothesis that pre-exposure to different photoperiods sets the state of the methylome and define the extent of tissue and cellular remodelling.

We will also investigate how a key molecular switch (Eya3), driving long-day thyroid hormone pathways may be drive other neuroendocrine circuits, and explore coupling between this long-day switch and the underlying seasonal methylome.

Our approaches employ bioinformatics, modeling, whole genome sequencing approaches and extensive biochemical methodologies, combined with whole-animals studies. The project capitalizes from access to a recent sequenced sheep genome through our role in the International Sheep Genome Consortium (ISGC), and will be the first study of how epigenetic mechanisms may regulate growth and reproduction in a mammal and livestock species.

This is an ambitious project, which addresses the role of epigenetic modification in regulating growth and reproduction in a seasonal mammal. Our discovery of a major imprinting centre operating in the neuroendocrine axis of a seasonal species has potentially enormous scientific significance, as well as practical relevance for animal breeding, and may reveal how an animal can respond and adapt to climate change.

At Roslin we have strong links with all Animal Breeding sectors, including ruminants and poultry. A clear application of our studies lies in the identification of target genes for marker-assisted selection. Through a link project with Affymetrix and Aviagen we have developed the first 600K high density genotyping array for whole genome selection in poultry. This technology offers a natural route for exploitation of genetic information in other species, including the sheep. Roslin is part of the International Sheep Genome Consortium providing sequence and gene annotations. Together these provide a natural route to disseminate and exploit epigenetic information from within this project to industry and the wider community. For example, there is currently much excitement about the possibility of exploiting genetic variation in epigenetic imprints, which may underpin genotype x environmental interactions. Our work will define the first methylome for a seasonal species. Effective uptake of our research in livestock is facilitated by close links with the Biosciences KTN and presentations to industry. This project has the potential to impact on the sustainability of the livestock industries in the UK and thus to inform DEFRA policy. It falls within the remit of the BBSRC Sustainable Agriculture Strategy Board and priority for research on Global Food Security.

There is considerable interest within "Pharma" in developing tools to regulate epigenetic processes from cancer to psychiatry. In Manchester existing links with GSK, including a free exchange of research staff, will allow access to novel compounds to test. For example, there is considerable interest in the role that epigenetic changes may play in the ageing process, but there are few good models - we may have identified such a model, involved in both hypothalamic and pituitary function. The other major site in the brain where melatonin receptors are localized is in the hippocampal region - a key structure involved in memory consolidation; of particular relevance to ageing. In man, shift work and non-circadian feeding times have profound metabolic consequences. This represents a wide-spread problem in society as it likely underpins health issues associated with long-term shift work. Our research could define quite novel epigenetic mechanisms in which rhythmic signals may control metabolic processes and help inform appropriate circadian management protocols with applications in healthy living and healthy ageing.

Both Manchester and Edinburgh are very active in public engagement with science. Andrew Loudon is an active participant in Public Understanding Activities and regularly gives open public lectures within the University of Manchester and to outside bodies including Café Scientifique and numerous other UK groups, and many BBC interviews. David Burt actively promotes the genomics and genetics of livestock and its applications in industry and medicine. Roslin is active in public engagement with a number of events within the University each year. These consist of lectures, open days to the public, school visits and projects for schools, undergraduate and postgraduate students. The wider significance of research is disseminated through papers, web sites, press releases and interviews on radio. Julian Davis as a clinical endocrinologist has regular contact with patients and carers, works with the Pituitary Foundation and the Clinical Committee of the Society for Endocrinology to promote research through its media and public relations offices.