Stem cell screening of human nutrient-gene interactions at the epigenetic level

Lead Research Organisation: University of Nottingham
Department Name: School of Medicine

Abstract

Scientific evidence indicates that the nutrients supplied by a pregnant mother to her fetus can influence genes in ways that may alter how fetal organs develop during pregnancy. This may lead to a range of later life diseases when her baby becomes an adult (including obesity, heart disease and diabetes). Mum's diet during pregnancy could affect the fertility of her children and perhaps even induce diseases that not only affect the mother's children but also her grandchildren and future generations. Studies have suggested that nutrients that can determine whether a specific gene is switched on or off at a time when specific organs are being formed may underlie how diet can alter development and cause disease. Each organ formed (such as the liver, heart and kidney's) requires a certain set of genes to be switched on or off at the correct time in development, This ensures that, for example, 'kidney' genes are not incorrectly switched on when the heart is being formed. This project aims to determine which combinations of nutrients may alter the chemistry of DNA to determine whether genes are properly or incorrectly turned on or off. These so-called 'epigenetic' changes could be 'good' or 'bad' at promoting healthy development. How nutrients affect the epigenetic chemistry of genes is not routinely assessed at present by the food industry, mainly because it is obviously not possible to experimentally feed pregnant women potentially damaging diets and other methods for assessing human cells have not yet been developed. Syngenta, other food companies and Governmental agencies who regulate food safety are aware of the potential for epigenetic effects that, if detected, could avoid some diseases. If they knew what type of safe foodstuffs to develop, or to advise us what is safest to eat, they could assist in improving the nations's health. There is now a need for developing an industrially-relevant tool that would allow us to robotically screen the many potential combinations and amounts of different foodstuffs that could affect our genes. This need has prompted our collaboration between the University of Nottingham and Syngenta, that also builds on the previous BBSRC funded work in Nottingham. The project will use human embryonic stem cells and liver cells derived from them to investigate the impact of nutrients and food additives on two human tissues that may be very susceptible to nutrient exposure. Before the availability of human embryonic stem cells, it was not possible to carry out routine experiments of this nature on the human embryo or liver. The embryo is of importance since major epigenetic changes occur in almost all genes at this stage as the embryo is about to make all of the cell types necessary to construct a fetus. It is well-documented in several mammals that embryonic cells are particularly vulnerable to epigenetic disruption that can profoundly alter development and lead to adult disease and so early pregnancy is an important time to assess. The liver is likely to be the organ of major importance in the fetus and adult, since 1) it is known to be the major site of producing chemical methyl groups to make epigenetic changes to genes 2) nutrients obtained from the diet are often converted to other chemical variants by the liver and so the liver may unravel diet-induced changes that are more likely to occur in the body, rather than in cells simply cultured in the laboratory.

Technical Summary

Increasingly epigenetic processes are being recognised as significant mediators of dietary programming, on subsequent health not only in individuals but in their offspring and even their offspring's progeny. The exact nature of these epigenetic processes and the nutrients that induce them remains a 'black box'. Due to the lack of a tractable human system to investigate the underlying mechanisms, this Industrial Partnership between the University of Nottingham and Syngenta aims to investigate the suitability of human embryonic stem cells (hESC) and their hepatocyte derivatives as novel platforms for assessing the epigenetically-based benefits and risks of micro-nutrients. The project will focus on nutrients that contribute to the methionine/folate metabolic cycles that are particularly active in embryonic cells and hepatocytes, since these cycles produce the methyl groups required for DNA and histone methylation. Using high throughput cell culture screens, a wide range of nutrient dose and exposure time combinations can be evaluated on a scale not previously possible. Combined with high throughput sequencing evaluation of the epigenome, comprehensive analysis of the nature and extent of nutritional programming on epigenetic methylation reactions will be evaluated. This will inform optimal dietary choices for improved health and provide industrially-relevant tools to help develop new foodstuffs in the biosafe manner that Government regulators require increasingly.

Publications

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Matsa E (2012) In vitro uses of human pluripotent stem cell-derived cardiomyocytes. in Journal of cardiovascular translational research

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Patel A (2016) High throughput screening for discovery of materials that control stem cell fate in Current Opinion in Solid State and Materials Science

 
Description robotic platform developed to secure academic and industrial collaborations e.g with Syngenta, GSK and Tokyo Electron
Exploitation Route academic and industrial collaborations
Sectors Healthcare

 
Description A final report was submitted to BBSRC by the PI. I do not have access to this as the PI left the university 2 years ago
First Year Of Impact 2011
Sector Healthcare
Impact Types Economic

 
Description Asha E-term fellowship
Amount £250,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 12/2013 
End 11/2015
 
Description BHF Centre for Regen Med
Amount £2,500,000 (GBP)
Funding ID P47352/ 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2017
 
Description BHF MyoD grant
Amount £300,000 (GBP)
Funding ID PG/14/59/31000 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2015 
End 05/2018
 
Description BHF Programme Grant (2 pilot with Sian Harding)
Amount £475,000 (GBP)
Funding ID RG/11/19/29264 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2012 
End 04/2014
 
Description BHF programme 2014-17
Amount £1,125,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2014 
End 04/2017
 
Description EPSRC equip - seahorse
Amount £115,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 09/2014 
End 03/2015
 
Description EU - dave
Amount £300,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 09/2012 
End 08/2015
 
Description Heart Res UK (Divya)
Amount £147,000 (GBP)
Funding ID TRP01/12 
Organisation Heart Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 01/2015
 
Description MRC capital equipment
Amount £714,000 (GBP)
Funding ID MR/L012618/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2013 
End 03/2014
 
Description NC3Rs main panel (Viola)
Amount £515,000 (GBP)
Funding ID NC/K000225/1 
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 02/2013 
End 02/2016
 
Description NC3Rs-CRACK-IT phase 1
Amount £100,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 12/2013 
End 06/2014
 
Description NC3Rs-CRACK-IT phase 2
Amount £1,000,000 (GBP)
Organisation National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) 
Sector Private
Country United Kingdom
Start 01/2015 
End 01/2018
 
Description University of Nottingham Strategic Development Fund "Nottingham Regenerative Medicine Centre" 1.1.15-31.12.18. £602,140 (PI)
Amount £602,000 (GBP)
Funding ID n/a 
Organisation University of Nottingham 
Sector Academic/University
Country United Kingdom
Start 11/2014 
End 10/2020
 
Description • BHF Programme Grant RG/15/6/31436: Predicting anti-arrhythmic drug efficacy from the divergent molecular basis of RyR2 dysfunction in genetic arrhythmia syndromes
Amount £1,100,000 (GBP)
Funding ID RG/15/6/31436 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2015 
End 09/2020
 
Description • BHF Special Project no. SP/15/9/31605. "Coupling gene targeted reporters with fully automated compound library screening to mature hPSC-cardiomyocytes".
Amount £1,100,000 (GBP)
Funding ID SP/15/9/31605 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 12/2019
 
Description • BIRAX grant 04BX14CDLG. Gene targeted optogenetics in hPSC-cardiovascular cells for transplantation into animal models of heart dysfunction. 1.9.15-31.8.18. £400K
Amount £400,000 (GBP)
Funding ID 04BX14CDLG 
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2018
 
Description • EPSRC Impact Accelerator Award. A Strategic Partnership with the Australian Cooperative Research Centre for Cell Therapy Manufacturing (CRC-CTM) to Commercialise Stem Cell Culture Polymers
Amount £67,000 (GBP)
Funding ID n/a 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 11/2015 
End 02/2017
 
Description • EPSRC Programme Grant EP/N006615/1: 'Next Generation Biomaterials Discovery'. PI: Morgan Alexander. Multiple Co-Is. 1.10.15-30.9.20. £6.6m
Amount £6,600,000 (GBP)
Funding ID EP/N006615/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2015 
End 09/2020
 
Description • MRC grant MR/M017354/1: MICA: Development of Metrics and Quality Standards for Scale up of Human Pluripotent Stem Cells. 1.5.15-30.4.17 £1.
Amount £1,200,000 (GBP)
Funding ID MR/M017354/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2015 
End 04/2017
 
Description Automation (Development of robot) 
Organisation Tecan UK Ltd
Country United Kingdom 
Sector Private 
PI Contribution Bespoke robotic platform for automated culture and differentiation of human stem cells
Collaborator Contribution Role in automation
Impact Publications, grants
Start Year 2010
 
Description BIRAX interactions (Mummery, Gepstein) 
Organisation Technion - Israel Institute of Technology
Country Israel 
Sector Academic/University 
PI Contribution New partnership between three labs
Collaborator Contribution Skills in progenitor cell biology and cell transplantation in vivo
Impact Early stage at present
Start Year 2015
 
Description CRACK-IT consortium 
Organisation GlaxoSmithKline (GSK)
Department Safety Assessment GSK
Country United Kingdom 
Sector Private 
PI Contribution consortium working on safety assessment
Collaborator Contribution all active contributors to researcher and academic input
Impact publications and grants
Start Year 2014
 
Description CRACK-IT consortium 
Organisation Leiden University
Country Netherlands 
Sector Academic/University 
PI Contribution consortium working on safety assessment
Collaborator Contribution all active contributors to researcher and academic input
Impact publications and grants
Start Year 2014
 
Description CRACK-IT consortium 
Organisation Pluriomics BV
Country Netherlands 
Sector Private 
PI Contribution consortium working on safety assessment
Collaborator Contribution all active contributors to researcher and academic input
Impact publications and grants
Start Year 2014
 
Description CRACK-IT consortium 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution consortium working on safety assessment
Collaborator Contribution all active contributors to researcher and academic input
Impact publications and grants
Start Year 2014
 
Description CRACK-IT consortium 
Organisation University of Hamburg
Country Germany 
Sector Academic/University 
PI Contribution consortium working on safety assessment
Collaborator Contribution all active contributors to researcher and academic input
Impact publications and grants
Start Year 2014
 
Description Industrial collaboration (GSK via CRACK-IT) 
Organisation GlaxoSmithKline (GSK)
Department Safety Assessment GSK
Country United Kingdom 
Sector Private 
PI Contribution Facilitated award of NC3Rs CRACK-IT grant
Collaborator Contribution Implicit in the sponsorship and construction of the challenge
Impact Financial, international collaboration, skills sharing, joint PhD students, researcher exchange
Start Year 2013
 
Description MRC-TEL consortium (Manchester, UKSCB, Sanger, TEL) 
Organisation National Institute for Biological Standards and Control (NIBSC)
Country United Kingdom 
Sector Public 
PI Contribution joint grant with industrial partner
Collaborator Contribution joint grant with industrial partner
Impact joint grant with industrial partner
Start Year 2015
 
Description MRC-TEL consortium (Manchester, UKSCB, Sanger, TEL) 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution joint grant with industrial partner
Collaborator Contribution joint grant with industrial partner
Impact joint grant with industrial partner
Start Year 2015
 
Description MRC-TEL consortium (Manchester, UKSCB, Sanger, TEL) 
Organisation Tokyo Electron
Country Japan 
Sector Private 
PI Contribution joint grant with industrial partner
Collaborator Contribution joint grant with industrial partner
Impact joint grant with industrial partner
Start Year 2015
 
Description MRC-TEL consortium (Manchester, UKSCB, Sanger, TEL) 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution joint grant with industrial partner
Collaborator Contribution joint grant with industrial partner
Impact joint grant with industrial partner
Start Year 2015
 
Description Maturation grant (Tinker, Smith, Fischer) 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution joint grant and development of equipment, new molecules, cell resources
Collaborator Contribution joint grant and development of equipment, new molecules, cell resources
Impact joint grant and development of equipment, new molecules, cell resources
Start Year 2015
 
Description Maturation grant (Tinker, Smith, Fischer) 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution joint grant and development of equipment, new molecules, cell resources
Collaborator Contribution joint grant and development of equipment, new molecules, cell resources
Impact joint grant and development of equipment, new molecules, cell resources
Start Year 2015
 
Description surface work (Morgan Alexander, Nottingham) 
Organisation University of Nottingham
Department School of Pharmacy
Country United Kingdom 
Sector Academic/University 
PI Contribution lead the stem cell work of this collaboration
Collaborator Contribution Multiple grant awards and papers
Impact grants and papers
Start Year 2010
 
Description syngenta 
Organisation Syngenta International AG
Country Global 
Sector Public 
PI Contribution stem cell automation
Collaborator Contribution intellectual and financial input
Impact advances in stem cell automation
Start Year 2009
 
Description Various presentations that Lisa, Yan and Roger did for BBSRC projects 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Presentations, workshops, posters, industrial engagement
Year(s) Of Engagement Activity 2012