Epigenetic control of seasonal timing
Lead Research Organisation:
University of Edinburgh
Department Name: The Roslin Institute
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
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.
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.
Planned Impact
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.
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.
Organisations
Publications
Wood SH
(2015)
Binary Switching of Calendar Cells in the Pituitary Defines the Phase of the Circannual Cycle in Mammals.
in Current biology : CB
West A
(2013)
Npas4 is activated by melatonin, and drives the clock gene Cry1 in the ovine pars tuberalis.
in Molecular endocrinology (Baltimore, Md.)
Wood SH
(2020)
Circadian clock mechanism driving mammalian photoperiodism.
in Nature communications
Wood SH
(2020)
Circadian clock mechanism driving mammalian photoperiodism.
in Nature communications
Wood S
(2014)
Clocks for all seasons: unwinding the roles and mechanisms of circadian and interval timers in the hypothalamus and pituitary.
in The Journal of endocrinology
Description | our aim was to understand the molecular basis of seasonal timing in sheep. In the research we have discovered transcriptional and epigenetic pathways that control seasonal timing. In particular a novel system of binary calendar cells that switch between long and short days, summer and winter. |
Exploitation Route | Genes and pathways can be used to define genetic targets in sheep for control of seasonal biology and possible drug targets in humans for seasonal disorders. |
Sectors | Agriculture, Food and Drink,Healthcare |
URL | http://www.ncbi.nlm.nih.gov/pubmed/26412130 |
Description | Biotek2021: The Atlantic salmon genome sequence as a tool for precision breeding |
Amount | kr 1,500,000 (NOK) |
Funding ID | Researcher project - BIOTEK2021 |
Organisation | Research Council of Norway |
Department | BIOTEK2021 |
Sector | Public |
Country | Norway |
Start | 02/2012 |
End | 02/2016 |
Description | HFSP Research Grants: Evolution of seasonal timers |
Amount | $1,200,000 (USD) |
Organisation | Human Frontier Science Program (HFSP) |
Sector | Charity/Non Profit |
Country | France |
Start | 11/2015 |
End | 12/2018 |
Description | Response Mode: Unravelling the networks that regulate seasonal rhythmicity in the epigenome |
Amount | £1,200,000 (GBP) |
Funding ID | BB/N015347/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2016 |
End | 12/2019 |
Description | Standard Grant Submissions - Epigenetic control of seasonal timing |
Amount | £1,700,000 (GBP) |
Funding ID | BB/K000764/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2012 |
End | 11/2016 |
Title | Epigenetic seasonal timing - Le Yu Datasets |
Description | Sequence files for genome and transcriptome. Raw reads and intermediary files. (SAM/BAM, Fastq, Fasta, etc.). ## Access ## This dataset is held in the Edinburgh DataVault, directly accessible only to authorised University of Edinburgh users. External users may request access to a copy of the data by contacting the Principal Investigator, Contact Person or Data Manager named on this page. University of Edinburgh users who wish to have direct access should consult the information about retrieving data from the DataVault at: http://www.ed.ac.uk/is/research-support/datavault . This dataset is too large for storage in the University's public online repository DataShare, or other prominent online archives. |
Type Of Material | Database/Collection of data |
Year Produced | 2019 |
Provided To Others? | Yes |
Description | Hosted female German Erasmus exchange student on 3 month work experience 'researcher shadowing' in my lab. |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Hosted female German Erasmus exchange student on 3 month work experience 'researcher shadowing' in my lab. Following her research experience she is going to apply for a masters or PhD program. |
Year(s) Of Engagement Activity | 2017 |
Description | Lightning talk & Poster at 64th NIBB Conference, Okazaki, Japan, 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Lighting talk and poster on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock". The conference prompted great interest and discussion from international leaders in seasonal biology. The conference led to concrete plans for collaboration on seasonal biology in Quail with Takashi Yoshimura's group in Japan. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.nibb.ac.jp/conf64/program.html |
Description | Open doors day |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Over 200 members of the public attended which sparked questions and discussion regarding our research |
Year(s) Of Engagement Activity | 2012,2013,2014,2015,2016,2017,2018 |
Description | Poster presentation Edinburgh Genomics Conference, Edinburgh, 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Presented poster on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock", which was awarded the poster prize. |
Year(s) Of Engagement Activity | 2016 |
Description | Poster presentation ISGC workshop PAGXXIV, San Diego, CA, USA, 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock". The poster prompted many questions from conference delegates from industry and academia. |
Year(s) Of Engagement Activity | 2015,2016 |
URL | http://www.nibb.ac.jp/conf64/pdf/Poster-Title.pdf |
Description | Projects Update Meeting regarding Circannual Clock in Lake District (With collaborators in University of Manchester, The Arctic University of Norway, and various interested emeritus professors) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Two days of talks, discussions and planning meetings with participants and scientific advisors regarding progress on sheep circannual related projects. |
Year(s) Of Engagement Activity | 2018 |
Description | Society for Research on Biological Rhythms (SRBR) meeting 2018 poster presentation (Amelia Island, FL, USA) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Poster presentation entitled: Genome-wide changes in DNA methylation mark the changing seasons in mammalian calendar cells. Reported on progress in seasonal changes in DNA CpH methylation determined by RRBS. |
Year(s) Of Engagement Activity | 2018 |
URL | https://srbr.org/meetings/upcoming-meeting/ |
Description | Talk ISGC workshop PAGXXV, San Diego, CA, USA, 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock" to the workshop organised by the International Sheep Genome Consortium. There were a number of questions and discussion as to how seasonal biology could be important in other agricultural traits (e.g. seasonal epigenetic control of salmon maturation). |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.intlpag.org/2017/program/workshop-list-xxv |
Description | Talk ISGC workshop PAGXXV, San Diego, CA, USA, 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | A talk on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock" to the workshop organized by the International Sheep Genome Consortium. This included an update on the current progress on genotyping/resequencing exotic breeds with seasonal phenotypes. There were a number of questions and discussion as to how seasonal biology could be important in other agricultural traits (e.g. seasonal epigenetic control of salmon maturation). |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.intlpag.org/2017/program/workshop-list-xxv |
Description | Talk at Cambridge Livestock Genomics Meeting, Cambridge, UK, 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Talk on "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock". The Livestock Genomics Meeting encompasses groups working across livestock species which provides invaluable incite into relevant work in other species and how our work is applicable to other traits of agricultural and economic importance. The talk prompted valuable discussion with groups working in the U.S. and Japan. |
Year(s) Of Engagement Activity | 2016 |
Description | Talk at Chromatin, Epigenetics & Gene Regulation meeting, Edinburgh, UK, 2016 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Talk on Seasonal methylation changes in the pituitary's calendar cells to the Edinburgh Chromatin, Epigenetics & Gene Regulation meeting. There were many questions and discussion as to whether methylation is the output or regulator of seasonal changes. |
Year(s) Of Engagement Activity | 2016 |
Description | Talk at the Roslin Computational Genetics Discussion Group |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Talk entitled "Genome Wide Transcript and Methylation Changes in the Sheep Seasonal Clock". There were useful questions on the status of EYA3 as a candidate seasonal regulator and discussion on the application of the work to breeding for seasonal phenotypes. An overview of the progress on resequencing exotic breeds was also discussed, which was of particular relevance to the genetics audience. |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.wiki.ed.ac.uk/display/RCG/Computational+Genetics+Discussion+Group |
Description | Talk: Epigenetics and seasonal biology at Wild Clocks Conference (Munich, Germany) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited by session chair to talk about our work on circannual ovine DNA methylation in the PT. There were many questions on the talk and considerable interest in our findings. |
Year(s) Of Engagement Activity | 2018 |
URL | https://www.orn.mpg.de/wild-clocks-conference |
Description | Transcriptional and Epigenetic Regulation of Seasonal Timing. |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Invited lecture: Transcriptional and Epigenetic Regulation of Seasonal Timing. In "Evolution of seasonal timers". The 64th NIBB Conference, Okazaki Conference Centre, Okazaki, Japan. 22-24 April, 2016. |
Year(s) Of Engagement Activity | 2016 |