Epigenetic regulation of gene expression as a mechanism of nutritional programming and developmental origins of health and disease

Lead Research Organisation: University of Cambridge
Department Name: Clinical Biochemistry

Abstract

The diet of an individual has important health issues at any stage of life - 'we are what we eat' after all. However, there is evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term implications on the health of her offspring - so, in some ways 'we also are what our mothers ate during pregnancy'. Normal term babies born from mothers with poor nutrition during pregnancy usually have a low weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as diabetes, hypertension and heart disease in adulthood. The underlying causes of the relationship between poor early growth and disease in adulthood are not known, but we believe that the quality of the diet of women during pregnancy is critically important. Many of our attempts to decipher mechanisms of human diseases both rely and benefit from studying animal models. We have shown in a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth and develop diabetes in adulthood. We have identified important genes in the pancreas that are expressed at low levels in the offspring of protein-restricted mothers compared to control animals. We now plan to study further these animals to understand how a restricted diet is able to perturb expression of key genes involved in pathogenesis of diabetes. We are particularly interested in studying epigenetic mechanisms - that is mechanisms able to change activity of a gene without altering its DNA sequence - that could be triggered by nutritional changes during pregnancy. We also want to know more precisely at which time/s during pregnancy the quality of the mother's diet is most important for giving birth to healthy babies. This will enable us to both identify at risk individuals and to develop intervention strategies to improve the health of both the pregnant women and their offspring.

Technical Summary

The human baby responds and adapts to the nutrients it receives during gestation and lactation in a variety of ways. These adaptations include metabolic and endocrine changes that may lead to life-long changes in the function and structure the body - a concept which has been termed fetal programming. The suggestion is that the baby receives from its mother a forecast of the nutritional environment it will receive after birth and modifies its metabolism, whole body physiology and growth trajectory appropriately to maximise its chances of survival postnatally. However these adaptations become detrimental if the conditions after birth are not the same as the ones encountered during early life. The inappropriate programming results in a considerably higher susceptibility to developing chronic diseases of adult life. This Developmental Origins of Health and Disease hypothesis proposes that disorders such as heart disease and type 2 diabetes may result from an imbalance between the environment experienced in utero and that experienced postnatally. This hypothesis has been supported by numerous epidemiological studies which have shown an association between low birth weight and later disease and also by studies in animals. The dominant research focus to date has been the defining of the physiological adaptations and metabolic changes in both human and animal studies. However, very few studies have addressed the molecular mechanisms by which a phenomenon that occurs in utero has a phenotypic consequence many years later. Epigenetics refers to covalent modifications of DNA and core histones which are heritable and affect genome function (transcription, recombination, replication) without altering the nucleotide sequence of DNA. Epigenetic mechanisms are essential for development and differentiation and create a 'memory' of cell identity. Importantly, epigenetic modifications can be modulated by nutritional factors and can act as reversible switches of gene expression to heritably maintain specific genomic regions in a transcriptionally silent or active state. Epigenetic regulation of gene expression is therefore an attractive candidate mechanism for fetal programming because it confers and maintains cellular 'memory' for many cell divisions. The aim of this proposal is to establish a mechanistic link between maternal diet during pregnancy, epigenetic states of the genome and the developmental origins of adult disease. Using an integrated approach combining molecular biology, whole animal nutritional programming and functional genomics, epigenomics on a defined cell type, the pancreatic beta cell, we will address the following issues. Firstly, we will establish if the epigenetic state of the genome can be altered due to nutritional programming in utero and if such changes can explain programmed changes in gene expression. Secondly, we will identify the critical time windows by which epigenetic memory and gene activity are established by fetal programming. Finally, we will manipulate DNA methylation of key metabolic genes in vitro and profile the transcriptional and metabolic consequences. We will achieve these aims using our well established maternal protein restriction model of fetal programming. Understanding the mechanisms involved in intrauterine nutritional programming could ultimately lead to diagnosis, prevention and potential treatment of long term effects of maternal diet on adult health.

Publications

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Ozanne SE (2007) Mechanisms of disease: the developmental origins of disease and the role of the epigenotype. in Nature clinical practice. Endocrinology & metabolism

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Reusens B (2007) Fetal determinants of type 2 diabetes. in Current drug targets

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Reusens B (2007) Fetal determinants of type 2 diabetes. in Current drug targets

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Sandovici I (2011) Maternal diet and aging alter the epigenetic control of a promoter-enhancer interaction at the Hnf4a gene in rat pancreatic islets. in Proceedings of the National Academy of Sciences of the United States of America

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Smith N (2006) Intrauterine origins of metabolic disease in Reviews in Gynaecological and Perinatal Practice

 
Description The diet of an individual has important health issues at any stage of life - "we are what we eat" after all. However, there is growing evidence to suggest that the diet of a pregnant woman is particularly important as it has major long-term implications for the health of her offspring - so, in some ways "we also are what our mothers ate during pregnancy". Normal term babies born from mothers with poor nutrition during pregnancy often have a low weight. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing various common diseases such as type 2 diabetes, high blood pressure and heart disease in adulthood. The underlying causes of the relationship between poor early growth and disease in adulthood are not known, but the quality of the diet of women during pregnancy is thought to be critically important. Many of our attempts to decipher mechanisms of human diseases both rely and benefit from studying animal models. We have shown in a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth and then develop type 2 diabetes in late adulthood. During the current project we have studied pancreatic islets (the cells in the body that produce insulin) from these animals before they get diabetes to work out why this happens. We identified a number of important genes that were not expressed properly in islets from the offspring of protein-restricted mothers compared to the islets from offspring of normally-fed (control) offspring. These genes are known to be important in determining how much insulin the islets can produce. We showed that as the animals get older expression of these genes in islets changes. This may explain why type 2 diabetes develops with age. The changes in gene expression with age were greater in the islets from offspring of the mothers who had a low protein diet during pregnancy suggesting that these animals were ageing faster. We also studied the DNA from the pancreatic islets to identify epigenetic changes that may explain why these islet genes are not expressed properly in the offspring of mothers who had a poor diet during pregnancy and why expression of these genes changes with age. Epigenetic modifications affect how much RNA and protein is made from a gene without altering the sequence of its DNA. The most common epigenetic modifications known to affect gene expression are DNA methylation and acetylation/methylation of histones (proteins that bind to DNA and affect activity of the gene). Using DNA from pancreatic islets in combination with studies using insulin secreting cell lines we identified alterations in these epigenetic marks that could explain why gene expression changed with age. We also identified changes in epigenetic marks that mediated the effect of poor nutrition during pregnancy on gene expression. These changes in gene expression and epigenetic modifications occurred before the development of type 2 diabetes therefore may represent markers of disease risk. These results will help us to identify individuals at risk of developing age-associated diseases such as type 2 diabetes and to develop new medicines to improve the health of both pregnant women and their offspring.
Exploitation Route Our novel findings proof of concept that promoter-enhancer interactions represent a novel target of nutritional programming. Future studies by us and others will address how widespread this mechanism is.
Sectors Other

 
Description 13th Insulin receptor and insulin action meeting. Programming by maternal over-nutrition: a developing obesity crisis. Nice France 20-22nd April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. 13th Insulin receptor and insulin action meeting. Programming by maternal over-nutrition: a developing obesity crisis. Nice France 20-22nd April 2017
Year(s) Of Engagement Activity 2017
 
Description 13th World Congress of Gynaecological Endocrinology, Florence, Italy, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: Pre-natal origins of adult metabolic syndrome

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
URL http://www.niab.com/uploads/files/NIAB_Synthetic_Hexaploid_Wheat.pdf
 
Description 17th IFCC-FESCC Euro Med Lab 2007, Amsterdam, The Netherlands, 2007 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: Foetal basis of adult disease

no actual impacts realised to date
Year(s) Of Engagement Activity 2007
URL http://www.brightsurf.com/news/headlines/93397/Efficient_treatment_a_step_closer_in_the_fight_agains...
 
Description 65th Nestle Workshop, Malaysia 
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 65th Nestle Nutrition Institution Workshop on the Importance of Growth for Health and Development, 29 March - 2nd April 2009, Kuala Lumpur, Malaysia
"Early growth and ageing"

NA
Year(s) Of Engagement Activity 2009
 
Description 7th Amazon Conference, Palermo, Sicily, Italy, Developmental origins of health and disease 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given - The role of the epigenome

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description 7th International Diabetes Federation Western Pacific Congress, Wellington, New Zeland, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: Developmetal origins of type 2 diabetes

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Annual meeting of the European Society for Paediatric Endocrinology, Istanbul, Turkey, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: Long-term consequences of early malnutrition

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Annual meeting of the Obesity Society, Phoenix, USA, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given: Lessons from rodent models - the role of early nutrition

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Biocenter Oulu Day 'Fifty Shades of Fat' conference, Oulu, Finland 23rd March 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker, Biocenter Oulu Day 'Fifty Shades of Fat' conference, 23rd March 2017, Oulu, Finland.
Year(s) Of Engagement Activity 2017
 
Description CUDOS conference on understanding molecular mechanisms underlying cardiovascular disease, diabetes, obesity and stroke, Doha, Qatar 10-12 April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. CUDOS conference on understanding molecular mechanisms underlying cardiovascular disease, diabetes, obesity and stroke. Nutritional programming of health and disease: are we ready to intervene? Doha, Qatar 10-12 April 2017
Year(s) Of Engagement Activity 2017
 
Description Consequences of maternal over-nutrition: mechanisms of hyperphagia and insulin resistance 
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 Talk given at the ILSI Europe roundtable Workshop on the effects of pre- and postnatal nutrition of infants of obese mothers: metabolic imprinting and later health outcomes, Brussels, Belgium

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Danone Scientific Symposium, 2009 
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 Talk given at the Danone Scientific Symposium on recent nutritional approaches for fighting two childhood epidemics of the 21st century: atopic diseases and obesity. "Developmental and epigenetic origins of obesity".

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Dept of Women's Health, Kings College London. 
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 Department of Women's Health, KCL, 11 March 2010, Kings College London
"You are what your mother ate: the developmental origins of type 2 diabetes and the metabolic syndrome"

NA
Year(s) Of Engagement Activity 2010
 
Description Developmental programming of metabolism-from global diabetes epidemiology to molecular mechanisms in animals and humans. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Taught PhD course in Copenhagen ;Programming of metabolism in rodents;

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Developmental programming of type 2 diabetes 
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 Talk given in Lund, Sweeden during the Epigenetics and the Environment: implications for behaviour and disease meeting

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Diabetes: lets save the next generation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Participants in your research or patient groups
Results and Impact Talk given at the OHSU Heart Research Centre 17th Annual Lecture, Portland, Oregon

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
URL http://www.abc.net.au/radionational/programs/scienceshow/genome-research---achievements-and-hopes/30...
 
Description Early growth and ageing 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk given at teh 65th Nestle Nutrition Institute Workshop on the importance of growth for the health and development, Kuala Lumpur, Malaysia

no actual impacts realised to date
Year(s) Of Engagement Activity 2009
 
Description Early nutrition and long term health - the role of epigenetic programming 
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 Talk given at the ESRC International Symposium on social science and epigenetics: opportunities and challenges, Edinburgh, Scotland

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description Epigenetic regulation of HNFalpha (MODY1) gene: role in developmental programming of type 2 diabetes 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Communication

no actual impacts realised to date
Year(s) Of Engagement Activity 2007
 
Description Epigenetics, neonatal environment and nutrition 
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 Talk given a the 10th Agricultural Biotechnology International Conference, Saskatoon, Canada

no actual impacts realised to date
Year(s) Of Engagement Activity 2010
 
Description Epigenetics: neonatal environmnet and nutrition: what are the consequences for tomorrow's human health 
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 Talk given at the 1st Alltech Epigenetics Symposium, Dunboyne, Ireland

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Experimental Biology conference 2017, Chicago, USA 22nd - 26th April 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker. Experimental Biology 2017 Epigenetics and the developmental origins of obesity, type 2 diabetes and cardiovascular disease: knowns, unknowns and possibilities. Chicago USA 22nd-26th April 2017
Year(s) Of Engagement Activity 2017
 
Description Human Nutrition Research Center (CRNH) Mtg, Clermont Ferrand, France 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Human Nutrition Research Center (CRNH), 28-29 May 2009, Clermont Ferrand, France
"Nutritional programming of type 2 diabetes, obesity and longevity"

NA
Year(s) Of Engagement Activity 2009
 
Description MSD Merck Diabetes Mtg, Seattle, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact MSD Merck Meeting, 17-19 April 2010, Seattle, USA
"Type 2 diabetes: Emerging Science"

NA
Year(s) Of Engagement Activity 2010
 
Description Maternal diet induced epigenetic changes and their implications for health 
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 Talk given at the 5th Congress of the International Society Of Nutrigenetics and Nutrigenomics, Beijing, China

no actual impacts realised to date
Year(s) Of Engagement Activity 2011
 
Description Media briefing at science centre in London 2011 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Extensive media coverage of the research internationally

On-going contact from multiple journalist
Year(s) Of Engagement Activity 2011
 
Description Nutricia Research Scientific Symposium Mechanisms of metabolic programming: what can we learn from translational research? Groningen, The Netherlands. 31st January 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited speaker.
Year(s) Of Engagement Activity 2017
 
Description Nutritionally programmed influences on gene expression - a mechanism underlying the developmental origins of health and disease. 
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 Talk given at the 6th Congress of the International Society of Nutrigenetics and Nutrigenomics (ISNN), Sao Paulo, Brazil

no actual impacts realised to date
Year(s) Of Engagement Activity 2012
 
Description OHSU Heart Research Center's Annual Lecture, Portland, Oregon, 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 OHSU Heart Research Center's Annual Lecture, 1 April 2012, Portland, Oregon, USA
You are what your mother ate: The developmental origins of type 2 diabetes and obesity"

NA
Year(s) Of Engagement Activity 2010
 
Description Otto Wolff Lecture at the Institute of Child Health, London,UK, 2007 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk: Foetal basis of adult disease

no actual impacts realised to date
Year(s) Of Engagement Activity 2007
 
Description Seminar Series MRI, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Seminar Series 2010 MRI, 12 May 2010, Cambridge
"Developmental programming and ageing"

NA
Year(s) Of Engagement Activity 2010
 
Description Society for Pediatric Research (SPR) Research Conference, Texas, USA, 2007 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach International
Primary Audience Other audiences
Results and Impact Talk given at the Society for Pediatric Research (SPR) Research Conference, Texas, USA "Nutritional manipulation throughout life in animal models"

no actual impacts realised to date
Year(s) Of Engagement Activity 2007
 
Description Society for the Developmental origins of health and disease workshop, Nottingham, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Models of type 2 diabetes

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Summer School, University of Angers. What is fetal programming? Angers, France 29th June 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Undergraduate students
Results and Impact University of Angers summer school. What is fetal programming? Angers, France 26th June - 7th July 2017
Year(s) Of Engagement Activity 2017
 
Description Symposia on the Developmental origins of health and disease aetologies, 2008 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation keynote/invited speaker
Geographic Reach National
Primary Audience Other audiences
Results and Impact Talk given at the Royal Society of Medicine

no actual impacts realised to date
Year(s) Of Engagement Activity 2008
 
Description Tea Talk Series, Dept of Zoology, Cambridge, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach Local
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Tea Talk Series, Dept of Zoology, 21 January 2010, Cambridge
"The developmental origins of type 2 diabetes and the metabolic syndrome"

NA
Year(s) Of Engagement Activity 2010