Nutrition and early life programming: exploring epigenetic mechanisms

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

Nutritional stresses in early life have long-lasting effects on health. Rapid growth in early postnatal life has been linked to increased incidence of common diseases such as obesity, cardiovascular disease and type 2 diabetes in later life. The mechanisms that link early post-natal nutrition with later ill health have not been well defined. Infants born preterm are encouraged to gain weight rapidly but this has important implications for adult health. By studying children who were born preterm, now aged 10-12 years, who participated in a post-natal nutritional trial we can glean important information not only about the health consequences of different infant feeding regimen, but also about the molecular mechanisms involved. This project aims to examine the molecular mechanisms that allow early nutrition to be 'memorised' at a cellular level. The genome is 'marked' in response to nutritional exposures and these markings can induce stable changes in which genes are switched on and switched off. Epigenetics refers to the decoration of the genome by these chemical markings and is an emerging field of post-genomic science. New technologies will be used to study epigenetic markings and gene expression in 120 children born preterm. These children took part in a nutritional trial and were fed one of three different diets from 36 weeks gestation to 6 months of age. Their growth and development has been followed over the last 10-12 years. Changes observed in epigenetic status and in gene expression will be related to differences in the health of the children, such as body composition, blood pressure, glucose and insulin levels and levels of hormones involved in fat metabolism. This project will use new tools in biotechnology and bioinformatics to study how nutrition influences the genome and how this may have long lasting effects on health.

Technical Summary

This proposal responds to the current BBSRC Joint Committee Priority on Developmental Origins of Optimal Health. It will examine variation in epigenetic marking, gene expression and biomarkers of metabolic health in children exposed to markedly different nutritional regimen in very early postnatal life and contribute to understanding the mechanisms linking adverse exposures in early life with common diseases such as obesity, cardiovascular disease and type 2 diabetes in later life. Nutritional stresses in early life have long-lasting effects on metabolism and health. Through work on animal models, epigenetic phenomena have been identified as a providing a potential candidate mechanism to explain this association. Early postnatal life offers a 'critical window' during which nutritional stresses can programme the subsequent health of an individual. By studying a cohort of infants born preterm and who participated in a randomised nutritional intervention trial of preterm and term formula feeding, we aim to investigate the role of epigenetic events in mediating persistent differential gene expression and altered health in children 10-12 years later. Epigenetic markings refer to chemical modifications to DNA and histone proteins that regulate transcriptional activity. This study will focus on DNA methylation. Techniques to detect and compare DNA methylation on a large scale have only been developed in recent years. This study will employ a microarray approach to screen for differences in DNA methylation and gene expression. Methylation differences at selected loci will be verified by quantitative, sequenced-based analysis using Pyrosequencing technology. Differential gene expression at selected loci will be quantified and verified using Real-Time PCR. This work exploits new high throughput technologies and builds on ongoing work in nutritional epigenomics.

Publications

10 25 50
 
Description This award fuelled early advances in the area of research in to the role of epigenetics in developmental programming. It set a solid foundation for future work in this area, evidenced by my extensive portfolio of epigenetics research.
Exploitation Route Further investigation of the role of epigenetics in developmental programming is ongoing.
The development and application of epidemiological approaches and more specifically, causal analysis methods in epigenetics is increasingly widespread.
Sectors Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description My published output has been cited (the main paper from this work has 86 cites) and the research conducted in this field has continued tom expand with further findings consolidating knowledge around the role of prenatal maternal body composition in offspring health being mediated by epigenetic effects.
First Year Of Impact 2010
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description ARIES - Accessible Resource for Integrated Epigenomic Studies
Amount £1,495,000 (GBP)
Funding ID BB/I025751/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 12/2013
 
Description Epigenetic signatures in fetal development
Amount £15,700 (GBP)
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Department Newcastle Healthcare Charity
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2011
 
Description Epigenetic studies on the ALSPAC Cohort
Amount £274,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 08/2013
 
Description Exploring epigenetic mechanisms in early life programming of obesity and other metabolic disorders
Amount £38,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2010 
End 11/2011
 
Description FQRNT Training Travel Bursary
Amount $13,900 (CAD)
Organisation Fonds Québécois de la Recherche sur la Nature et les Technologies 
Sector Charity/Non Profit
Country Unknown
Start 06/2010 
End 12/2010
 
Description Genomic and Epigenomic Complex Disease Epidemiology (GEoCoDE)
Amount € 875,000 (EUR)
Funding ID 247642 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2010 
End 12/2013
 
Description Study of transplacental drug transfer to the developing human fetus and an investigation into possible teratogenic mechanisms
Amount £35,000 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2010 
End 12/2011
 
Description The Avon Longitudinal study of parents and children: an international resource for population genomics and lifecourse epidemiology core programme support
Amount £6,000,000 (GBP)
Funding ID MC_PC_15018 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2011 
End 12/2013
 
Description American PsychoPathological Association 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote Speaker: dissemination of information followed by questions and discussion

Considerable interest resulted. Review article invited
Year(s) Of Engagement Activity 2012
 
Description Brazilian Epidemiology Congress, Sao Paolo, Brazil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Symposium - Brazilian Epidemiology Congress, Sao Paolo, Brazil - Dissemination of information followed by questions and discussion

Large international reach (>7,000 delegates)
Year(s) Of Engagement Activity 2011
 
Description Epigenetics Symposium, CELSE, Cyprus 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of information followed by discussion and questions

Informed discussion
Year(s) Of Engagement Activity 2010
 
Description Epigenetics and developmental programming conference, Newcastle 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of information, questions and discussion

First such conference which was well received and brought together population health epigenetics community
Year(s) Of Engagement Activity 2011
 
Description From the Complex Aetiology of Diseases to Translational Strategies Workshop, Sao Paolo, Brazil 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Plenary: From the Complex Aetiology of Diseases to Translational Strategies Workshop, University of Sao Paolo, Brazil : Dissemination of information followed by questions and discussion

Extensive coverage of workshop across Brazil
Year(s) Of Engagement Activity 2013
 
Description GEoCoDE International Workshop Newcastle 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Networking, questions and discussion

Raised awareness of research being undertaken by other participating institutes
Year(s) Of Engagement Activity 2011
 
Description Genomic and Epigenomic Studies in India 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Discussion and questions

Propvided training otherwise unavailable to Indian research community
Year(s) Of Engagement Activity 2009
 
Description Lecture Centre for Cellular and Molecular Biology Hyderabad April 2009 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussioin

Increased awareness, consolidated GEoCoDE Links - (Genetic and Epigenetic Complex Disease Epidemiology EU Programme)
Year(s) Of Engagement Activity 2009
 
Description Lecture Centre for Cellular and Molecular Biology, Hyderbad December 2009 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by quesions and discussion

Built staff exchange links - GEoCoDE Programme
Year(s) Of Engagement Activity 2009
 
Description Lecture Conference of Epidemiological Longitudinal Studies in Europe, Paphos, Cyprus 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Raised awareness of epidemiological methods for epigenetic use
Year(s) Of Engagement Activity 2010
 
Description Lecture EU Science and Humanities Sumer School on Nutrition and Ageing, Rimini 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion to a non-specialist (largely humjanities) audience

Raised awareness of subject matter
Year(s) Of Engagement Activity 2010
 
Description Lecture Institute for Genomics and Integrative Biology Delhi 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Stimulated discussion and debate. Developed academic links
Year(s) Of Engagement Activity 2009
 
Description Lecture King Edward Memorial Hospital Pune 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Increased awareness, consolidate GEoCoDE Programme Links
Year(s) Of Engagement Activity 2009
 
Description Merck, Rahway, New Jersey, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Collaboration discussed
Year(s) Of Engagement Activity 2011
 
Description Perinatal Society of Australia and New Zealand Meeting, Adelaide, Australia 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Keynote Speaker: Perinatal Society of Australia and New Zealand Meeting - Dissemination of information followed by questions and discussion

Raised issues and awareness in field
Year(s) Of Engagement Activity 2013
 
Description Plenary Nutrigenomics Week, Montecatini 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of information followed by questions and discussion

Increased awareness of subject
Year(s) Of Engagement Activity 2009
 
Description SNEHA/MRC 16th Annual Meeting Developmental Origins of Health and Disease, Hyderabad 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of information followed by quesions and discussion

New links with Indian colleagues established
Year(s) Of Engagement Activity 2012
 
Description Seminar Institute of Child Health UCL 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dessimination of information followed by questions and discussion

Dissemination of information stimulated discussion and debate
Year(s) Of Engagement Activity 2008
 
Description Seminar International Agency for Research on Cancer Lyon 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Health professionals
Results and Impact Dissemination of information followed by questions and discussion

Grant proposals followed
Year(s) Of Engagement Activity 2009
 
Description Seminar National Perinatal Epidemiology Unit Oxford University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Stimulated discussion and debate
Year(s) Of Engagement Activity 2008
 
Description Seminar Peninsula Medical School Exeter 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Dissemination of information followed by questions and discussion

Raised awareness of subject and current research
Year(s) Of Engagement Activity 2010
 
Description Seminar St Bartholomew's and the London Hospital 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by quesitons and discussion

Raised awareness of challenges of epigenetic epidemiology. Discussed collaboration
Year(s) Of Engagement Activity 2009
 
Description Symposium MRC Centre for Causal Analyses in Translational Epidemiology Bristol University 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of information followed by questions and discussion

Sparked discussion and questions to go forward
Year(s) Of Engagement Activity 2009
 
Description University of Cape Town - GEoCoDE Programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Staff exchanges and collaboration planned
Year(s) Of Engagement Activity 2011
 
Description University of Witwatersrand - GEoCoDE Programme 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Dissemination of information followed by questions and discussion

Staff exchanges and collaboration planned
Year(s) Of Engagement Activity 2011