DNA Methylation Developmental Programming and Cellular Memory: The Molecular Consequences of Folate Depletion In Utero
Lead Research Organisation:
Newcastle University
Department Name: Clinical Medical Sciences
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.
People |
ORCID iD |
John Mathers (Principal Investigator) | |
Dianne Ford (Co-Investigator) |
Publications
Wakeling LA
(2015)
SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing.
in Human genomics
Potter C
(2013)
Influence of DNMT genotype on global and site specific DNA methylation patterns in neonates and pregnant women.
in PloS one
Palou M
(2011)
Protective effects of leptin during the suckling period against later obesity may be associated with changes in promoter methylation of the hypothalamic pro-opiomelanocortin gene.
in The British journal of nutrition
McKay JA
(2011)
Diet induced epigenetic changes and their implications for health.
in Acta physiologica (Oxford, England)
McKay JA
(2016)
Maternal folate deficiency and metabolic dysfunction in offspring.
in The Proceedings of the Nutrition Society
McKay JA
(2014)
Metabolic effects of a high-fat diet post-weaning after low maternal dietary folate during pregnancy and lactation.
in Molecular nutrition & food research
McKay JA
(2011)
Effect of maternal and post-weaning folate supply on gene-specific DNA methylation in the small intestine of weaning and adult apc and wild type mice.
in Frontiers in genetics
McKay JA
(2011)
Folate depletion during pregnancy and lactation reduces genomic DNA methylation in murine adult offspring.
in Genes & nutrition
McKay JA
(2016)
Gene promoter DNA methylation patterns have a limited role in orchestrating transcriptional changes in the fetal liver in response to maternal folate depletion during pregnancy.
in Molecular nutrition & food research
McKay JA
(2017)
Maternal folate depletion during early development and high fat feeding from weaning elicit similar changes in gene expression, but not in DNA methylation, in adult offspring.
in Molecular nutrition & food research
McKay JA
(2016)
Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion.
in Nutrients
McKay JA
(2011)
Blood as a surrogate marker for tissue-specific DNA methylation and changes due to folate depletion in post-partum female mice.
in Molecular nutrition & food research
McKay J
(2011)
Maternal folate supply and sex influence gene-specific DNA methylation in the fetal gut
in Molecular Nutrition & Food Research
Mathers JC
(2009)
Epigenetics - potential contribution to fetal programming.
in Advances in experimental medicine and biology
Mathers JC
(2017)
Nutrigenomics in the modern era.
in The Proceedings of the Nutrition Society
Lisanti S
(2012)
Standardization and quality controls for the methylated DNA immunoprecipitation technique.
in Epigenetics
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
Langie S
(2014)
Redox and epigenetic regulation of the APE1 gene in the hippocampus of piglets: The effect of early life exposures
in DNA Repair
Kok DE
(2022)
Impact of In Utero Folate Exposure on DNA Methylation and Its Potential Relevance for Later-Life Health-Evidence from Mouse Models Translated to Human Cohorts.
in Molecular nutrition & food research
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 | JPI-HDHL - "Nutrition & The Epigenome" - Mid-term Symposium |
Geographic Reach | Europe |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://www.healthydietforhealthylife.eu/ |
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 | 08/2012 |
End | 09/2013 |
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 | 02/2012 |
End | 01/2013 |
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/ |