DNA Methylation Developmental Programming and Cellular Memory: The Molecular Consequences of Folate Depletion In Utero

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

Abstract

Summary Poor maternal nutrition can have profound effects on the long-term health and wellbeing of offspring and may cause premature ageing. These adverse effects on health include common diseases such as obesity, type 2 diabetes and cardiovascular disease. The risk of these conditions appears to be exacerbated when the offspring gain weight more quickly than would have been expected. In preliminary studies, we observed that mice born to mothers given diets low in folate (a B vitamin) during pregnancy and lactation became heavier adults than those born to mothers with normal folate supply despite the fact that there were no differences in body weight between the two groups of mice at weaning and that all mice received the same diet from weaning. This suggests that the maternal nutritional insult was 'remembered' by the mouse tissues and expressed as more rapid growth. Change in epigenetic markings is one of the most important mechanisms believed to be responsible for cellular 'memorisation' of early life experiences. Epigenetics describes chemical changes to the genome which regulate when and where genes are expressed (turned on) but which do not alter the primary DNA sequence. The best understood of the epigenetic marks is DNA methylation i.e. the addition of CH3 (methyl) groups to DNA. In our mouse studies we found that there were fewer CH3 groups in the DNA from adult mice born to the folate-depleted mothers. In follow up studies we have found that maternal folate depletion resulted in altered expression of over 600 genes in fetal liver. In this project we will investigate in more detail the effects of low maternal folate supply on growth and body fatness of the offspring and we will examine the effects of feeding high v. low fat diets from weaning. We anticipate that the high fat diet (based on the composition of Western human diets) will exacerbate the effects of the maternal nutritional insult. We will use state-of-the-art magnetic resonance imaging to allow us to measure how much fat is in the live mice and in which parts of the body it is stored. In humans, fat stored in the abdomen is associated with higher risk of several common disease including type 2 diabetes, cardiovascular disease and bowel cancer. We will then explore the mechanisms responsible for these phenotypic changes. We will focus on identification of genes whose expression has been changed through altered epigenetic markings and attempt to elucidate the molecular events leading to the genes being switched off, or switched on, inappropriately.

Technical Summary

An accumulating body of evidence supports the premise that nutritional deprivation in utero has lifelong consequences for health, including a predisposition to obesity, cardiovascular disease and type 2 diabetes, particularly in association with a plentiful food supply post-weaning. Thus, it is presumed that nutritional status in utero is recorded and remembered in a manner that programmes the foetus to use nutrients in a way that improves survival when the nutrient supply is poor but to be adapted inappropriately to a plentiful or excessive intake. Epigenetic processes, including DNA methylation, provide a compelling mechanism for such effects, manifest through influences on gene expression. Our preliminary data reveal that folate depletion in utero in the mouse did not affect weight at weaning but increased the weight of offspring at 100 d and induced global DNA hypomethylation in liver and affected expression of multiple genes in foetal liver. These observations provide the impetus to examine in detail the influence of this nutritional stress on adiposity and on the methylation and expression of specific genes. Our hypotheses are that i) folate depletion in utero predisposes mice to increased weight and abdominal adiposity in adulthood, exacerbated by a high-fat post-weaning diet and ii) the effect is mediated through the methylation of specific genes, which affects expression through transcription factor binding. These hypotheses will be investigated through measuring the effect of folate depletion in utero in mice, followed by a control or high-fat post-weaning diet, on weight gain and adiposity and by examining effects at late gestation on DNA methylation in liver, using a microarray-based approach, and on gene expression and DNA methylation at 180 d. Effects of promoter methylation on gene expression and transcription factor binding will be investigated for selected differentially methylated and expressed genes using in vitro molecular approaches.

Publications

10 25 50

publication icon
Langie SA (2013) Maternal folate depletion and high-fat feeding from weaning affects DNA methylation and DNA repair in brain of adult offspring. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

publication icon
Mathers JC (2017) Nutrigenomics in the modern era. in The Proceedings of the Nutrition Society

publication icon
Mathers JC (2009) Epigenetics - potential contribution to fetal programming. in Advances in experimental medicine and biology

publication icon
McKay JA (2016) Maternal folate deficiency and metabolic dysfunction in offspring. in The Proceedings of the Nutrition Society

 
Description We have observed that a nutritional insult in early life (low supply of folate (a B vitamin) to mothers before and during pregnancy and during lactation) appears to have long-term adverse consequences for the adult offspring. In addition, such nutritional depletion during development appears to exacerbate the effects of later insults specifically exposure to a high fat diet. We have observed that such insults may reduce the ability of the brain to repair damage to DNA.
Exploitation Route Our observation that early life nutritional may reduce the ability of the brain to repair damage to DNA may be of importance for the development of neurodegenerative diseases e.g dementia. Our findings could be taken forward by others to investigate i) the biological mechanisms responsible for these observations and ii) how to optimise early life nutrition to protect the brain during ageing.
Sectors Agriculture, Food and Drink,Healthcare

 
Description Co-chair of Workshop - ESRC/BBSRC Epigenetics Showcase. London. May 2019
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
URL https://bbsrc.ukri.org/news/events/2019/1905-epigenetics-showcase/
 
Description JPI-HDHL - "Nutrition & The Epigenome" - Mid-term Symposium
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
URL https://www.healthydietforhealthylife.eu/
 
Description MRC Nutrition and Health Review Workshop, 7th - 8th July 2016
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description MRC Review of Nutrition and Human Health Research, 14 Oct 2016
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description MRC Review of Nutrition and Human Health research - 17th March
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description Influence of folate intake during development and early life on epigenetic aberrations associated with childhood acute lymphoblastic leukaemia
Amount £13,084 (GBP)
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Department Newcastle Healthcare Charity
Sector Charity/Non Profit
Country United Kingdom
Start 02/2012 
End 01/2013
 
Description Influence of folate intake during development and early life on epigenetic aberrations associated with childhood acute lymphoblastic leukaemia
Amount £13,084 (GBP)
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust 
Department Newcastle Healthcare Charity
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 09/2013
 
Description Academic collaboration 
Organisation Ocera Therapeutics
Country United States 
Sector Private 
PI Contribution Collaboration between primary research laboratory and expert bioinformatic team to analyse and interpret resultant data from the project.
Collaborator Contribution Development and implementation of a bioinformatics pipeline for the analysis and interpretation of DNA methylation data.
Impact McKay JA, Adriaens ME, Ford D, Relton CL, Evelo CT, Mathers JC. Genes Nutr. 2008 Dec;3(3-4):167-71. Bioinformatic interrogation of expression array data to identify nutritionally regulated genes potentially modulated by DNA methylation.
Start Year 2009
 
Description Epigenetics Matters: Public Engagement Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact More than 50 participants attended the lecture. This led to discussion with several research groups afterwards.
Year(s) Of Engagement Activity 2018
 
Description Mini-symposium on Developmental Programming of Human Disease: Preconception Nutrition and Lifelong Health. Cumbria 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact JCM to provide
Year(s) Of Engagement Activity 2016
 
Description NuGO participants Assembly. Denmark 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Discussion among representatives of European universities and research institutes on how best to promote nutrigenomics research
Year(s) Of Engagement Activity 2016
 
Description NuGOweek 2017, Varna. August 2017 
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 Discussion of future strategis for research in the area of nutritional genomics
Year(s) Of Engagement Activity 2017
URL http://www.nugo.org/nugo-week/nugoweek-2017/