Impact of maternal diet on the epigenome and potentially modifiable effects on offspring health

Lead Research Organisation: MRC Unit, The Gambia

Abstract

We have discovered that babies born at different times of year in rural Gambia have differences in chemical marks (methylation) on their DNA that affect the way in which genes are expressed. The biggest difference occurs in a region (VTRNA2-1) that is predicted to be a critical determinant of immune function as well as being a tumour suppressor gene. In this project we will extend our analysis in three important directions: a) to gather data on many more pregnancies and offspring to better determine the times of year at which the labelling of this gene is most variable (this will help to inform us about the environmental/nutritional factors that cause such variations); b) to undertake detailed cellular studies to examine whether the consequences of these epigenetic changes are in line with those predicted from previous studies; and c) to start working towards the development of a possible nutritional intervention for mothers planning to become pregnant that we hope would reduce the frequency of disrupted patterns of epigenomic methylation.

Technical Summary

We have discovered that methylation at a key region affecting an imprinted gene expressing a non-coding RNA (VTRNA2-1 also termed nc886) is strongly affected by the season at which a baby is conceived. The evidence points to variations in maternal diet (and hence a mother’s methyl donor metabolome) as being responsible; when methyl donor supply is poor, resulting in a displacement of the intermediary pathways driving methylation (especially the SAM/SAH ratio), there is a higher frequency of offspring showing loss of imprinting. This project has 3 key aims: Aim 1: Extend our analysis of VTRNA2-1 methylation to include 700+ additional mother/infant pairs to better characterise the periods of critical exposure. This will help to refine our insights into the maternal nutritional exposures responsible for loss of imprinting. We will extend our analysis of the maternal methyl donor metabolome to an additional 350 mothers and an extended panel of nutrients and intermediary markers. We will then work with in silico modellers to establish which are the critical drivers of methylation variation; Aim 2: Examine the implications of imprinting or loss of imprinting at VTRNA2-1 on gene expression and cellular function using a recall-by-epigenotype methodology; Aim 3: To design a nutriceutical intervention to prevent disrupted DNA methylation. This aim will be based on insights gained from Aim 1 and will perform small scale preliminary interventions in small groups of non-pregnant women in preparation for anticipated large scale trials.

Planned Impact

We are optimistic that our proposed research can have a very high level of impact with potential implications for future
children worldwide. Our current analyses (summarised in the Case for Support) strongly suggest that we have
serendipitously discovered a link between pre- and peri-conceptional environmental exposures (with diet being the leading
candidate) and instability in the normal processes of DNA methylation leading to epigenetic errors. Such errors are known
to lead to many pathologic syndromes arising from developmental defects and these are likely to be the tip of an iceberg. If,
as our data suggest, a mother's nutritional status at conception can cause a permanent disruption of methylation at
differentially methylated regions in imprinted genes, allele-specifically expressed genes and metastable epialleles, then
there is a very high likelihood that these could be linked to a wide range of 'disordered' phenotypes. The fact that our most
susceptible candidate gene is a tumour suppressor gene that also plays a central role in regulating immunometabolism
provides an indication of the potential significance of our work. The implications are that by correcting a woman's methyl
donor status prior to conception we could greatly reduce epigenetic instability and avoid a large proportion of methylation errors. It is conceivable that such errors contribute to a wide range of avoidable pathologies, sub-clinical syndromes and
disease susceptibility traits. For instance, imprinted genes play an active role in fetal and placental development and
imprinting errors are already known to cause a host of developmental abnormalities. We speculate that they may influence
traits such as intra-uterine growth retardation (IUGR) and pre-term birth (PTB) that, whilst less severe for the individual,
represent enormous burdens of disease on a worldwide basis.
Who will benefit from this research? a) Parents worldwide who are planning a family. Note that folic acid is already widely
promoted and there are many supplement formulations marketed to mothers-to-be, but our data suggest that folic acid
alone is not sufficient and other supplements are purely empirical and lack an evidence base; b) Governments and their
health systems. Although is is premature to make such claims it is not inconceivable that reducing epigenetic errors by
improving mothers' preconceptional nutritional status could reduce the prevalence of a wide range of diseases that affect
the health, wealth and well-being of populations.
How will they benefit from this research? Our ultimate vision is to be able to formulate appropriate foods and/or
supplements to optimise the metabolic machinery necessary for appropriate DNA methylation during early embryonic and
fetal development. These could be promoted to mothers-to-be through multiple routes; either commercially or noncommercial.
There is a strong chance that a 'one-size-fits-all' solution may not work and that supplements would need to be
targeted by country, population groups, ethnicity, etc or even formulated for each woman. Our in silico modelling of nutrient
effects on methyl donor pathways will be important in inserting this question and in designing a range of supplements to
suit different population groups.

Publications

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Eriksen KG (2017) Influence of intergenerational parental energy and nutrient restriction on offspring growth in rural Gambia. in FASEB journal : official publication of the Federation of American Societies for Experimental Biology

 
Description Chairman - Strategic Advisory Board American Society of Nutrition
Geographic Reach North America 
Policy Influence Type Participation in a advisory committee
Impact Planning the ASN's future for Vision 2028
 
Description Wellcome Trust ERG 6
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact Deliberates on research funding with direct health outputs
 
Description Newton Fund MRC Joint Research Programme: Women's and Children's Health
Amount £928,853 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2015 
End 06/2018
 
Description Unsolicited approach
Amount $350,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 06/2015 
End 06/2017
 
Title West Kiang DSS 
Description Demographic Surveilance System for West Kiang Region 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? Yes  
Impact Forms the platform for all studies we conduct and creates novel research findings through secondary analyses. 
 
Title Submission of epigenomic data to public databases 
Description We upload all our epigenetic analyses to public databases 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact Not yet known 
 
Description Aflatoxin studies 
Organisation International Agency for Research on Cancer (IARC)
Country France 
Sector Public 
PI Contribution Provision of study site and samples
Collaborator Contribution IARC - epigenetic analysis UoL/QUB - aflatoxin analyses
Impact None yet
Start Year 2011
 
Description Aflatoxin studies 
Organisation Queen's University Belfast
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of study site and samples
Collaborator Contribution IARC - epigenetic analysis UoL/QUB - aflatoxin analyses
Impact None yet
Start Year 2011
 
Description Aflatoxin studies 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Provision of study site and samples
Collaborator Contribution IARC - epigenetic analysis UoL/QUB - aflatoxin analyses
Impact None yet
Start Year 2011
 
Description African Partnership for Chronic Disease / H3Africa 
Organisation H3Africa
Country United States 
Sector Charity/Non Profit 
PI Contribution Participation in Research partnership to assess the burden and aetiology of non-communicable diseases (NCDs) in sub-Saharan Africa (SSA), with a focus on genetic epidemiology
Collaborator Contribution Coordination of research projects across multiple sites, provision of a platform for interventional research in NCDs, ensureing that African populations benefit from the ongoing advances in genomics.
Impact None yet
Start Year 2012
 
Description African Partnership for Chronic Disease / H3Africa 
Organisation University of Cambridge
Department Department of Public Health and Primary Care
Country United Kingdom 
Sector Academic/University 
PI Contribution Participation in Research partnership to assess the burden and aetiology of non-communicable diseases (NCDs) in sub-Saharan Africa (SSA), with a focus on genetic epidemiology
Collaborator Contribution Coordination of research projects across multiple sites, provision of a platform for interventional research in NCDs, ensureing that African populations benefit from the ongoing advances in genomics.
Impact None yet
Start Year 2012
 
Description African Partnership for Chronic Disease / H3Africa 
Organisation University of the Gambia
Country Gambia 
Sector Academic/University 
PI Contribution Participation in Research partnership to assess the burden and aetiology of non-communicable diseases (NCDs) in sub-Saharan Africa (SSA), with a focus on genetic epidemiology
Collaborator Contribution Coordination of research projects across multiple sites, provision of a platform for interventional research in NCDs, ensureing that African populations benefit from the ongoing advances in genomics.
Impact None yet
Start Year 2012
 
Description Epigenetics and telomere length 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the research setting and samples and hypotheses.
Collaborator Contribution Dr Jess Buxton brings expertise and methods training.
Impact None yet.
Start Year 2015
 
Description Maternal nutrition and offspring miRNAs 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide the research setting, samples and manpower. We sought and successfully achieved additional funds from the Bill Melinda Gates Foundation to support this work.
Collaborator Contribution Dr Sarah Finer at QMUL brings expertise in miRNA programming an training in lab methods.
Impact None yet.
Start Year 2015
 
Description BBC documentary 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact We featured prominently in the BBC 2 documentary: 'Countdown to Life: The Extraordinary Making of You'
Year(s) Of Engagement Activity 2015
URL http://www.bbc.co.uk/programmes/b06crff1
 
Description ING website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact ING now has it's own website, where key news items are posted regularly.

The website is a vital point of information to ING's research activities.
Year(s) Of Engagement Activity 2012
 
Description International press coverage 
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 Following a press release we achieved worldwide media coverage for our latest epigenetic studies.
Year(s) Of Engagement Activity 2015
URL http://ing.mrc.ac.uk/home/news/
 
Description MRC Centenary Events @ UCL 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 500 attendees across a wide range of the public plus other academics

Wider interest and knowledge of MRC activities
Year(s) Of Engagement Activity 2013
 
Description MRC Festival 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact MRC Festival is an Annual Showcase of MRC Unit The Gambia's activities
Year(s) Of Engagement Activity 2016
 
Description MRC UCL Open Day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact ING participated in the UCL Centenary event, targeted at the general public but also including scientists from other MRC Units and groups in London. ING contribution included a formal lecture by Prof Prentice plus stands and exhibitions highlighting our work in Keneba.

Publicity in local London area.
Year(s) Of Engagement Activity 2013
 
Description Open Day (Gambia) 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Open Day in Keneba
Year(s) Of Engagement Activity 2016
 
Description Open days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Open day

Continued good relations with surrounding villagers who participate in our research
Year(s) Of Engagement Activity 2007,2008,2013,2014
 
Description Podcast 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Contribution to podcast

Multiple
Year(s) Of Engagement Activity 2009,2014
 
Description Public lecture 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Open Lecture to general audience including politicians

Improved profile
Year(s) Of Engagement Activity 2008,2013
 
Description Radio interview 
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 Public/other audiences
Results and Impact BBC World Service interview

None.
Year(s) Of Engagement Activity 2009,2014