Stem cell screening of human nutrient-gene interactions at the epigenetic level
Lead Research Organisation:
University of Nottingham
Department Name: School of Clinical Sciences
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.
Organisations
- University of Nottingham (Lead Research Organisation)
- Technion - Israel Institute of Technology (Collaboration)
- Leiden University (Collaboration)
- University of Manchester (Collaboration)
- UNIVERSITY OF NOTTINGHAM (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- National Institute for Biological Standards and Control (NIBSC) (Collaboration)
- Tecan UK Ltd (Collaboration)
- QUEEN MARY UNIVERSITY OF LONDON (Collaboration)
- Syngenta International AG (Collaboration)
- Tokyo Electron (Collaboration)
- UNIVERSITY OF GLASGOW (Collaboration)
- Universität Hamburg (Collaboration)
- Pluriomics BV (Collaboration)
- GlaxoSmithKline (GSK) (Collaboration)
- Stellenbosch University (Project Partner)
Publications
Celiz AD
(2015)
Discovery of a Novel Polymer for Human Pluripotent Stem Cell Expansion and Multilineage Differentiation.
in Advanced materials (Deerfield Beach, Fla.)
Denning C
(2016)
Cardiomyocytes from human pluripotent stem cells: From laboratory curiosity to industrial biomedical platform.
in Biochimica et biophysica acta
Dick E
(2013)
Exon skipping and gene transfer restore dystrophin expression in hiPSC-cardiomyocytes harbouring DMD mutations.
in Stem cells and development
Goldring C
(2017)
Stem cell-derived models to improve mechanistic understanding and prediction of human drug-induced liver injury.
in Hepatology (Baltimore, Md.)
Hammad M
(2016)
Identification of polymer surface adsorbed proteins implicated in pluripotent human embryonic stem cell expansion.
in Biomaterials science
Matsa E
(2012)
In vitro uses of human pluripotent stem cell-derived cardiomyocytes.
in Journal of cardiovascular translational research
Matsa E
(2014)
Allele-specific RNA interference rescues the long-QT syndrome phenotype in human-induced pluripotency stem cell cardiomyocytes.
in European heart journal
Patel A
(2016)
High throughput screening for discovery of materials that control stem cell fate
in Current Opinion in Solid State and Materials Science
Rajamohan D
(2013)
Current status of drug screening and disease modelling in human pluripotent stem cells.
in BioEssays : news and reviews in molecular, cellular and developmental biology
Rajamohan D
(2016)
Automated Electrophysiological and Pharmacological Evaluation of Human Pluripotent Stem Cell-Derived Cardiomyocytes.
in Stem cells and development
Smith JG
(2015)
Scaling human pluripotent stem cell expansion and differentiation: are cell factories becoming a reality?
in Regenerative medicine
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 | Public |
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 | 09/2013 |
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 | 04/2015 |
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 | 03/2012 |
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 | 03/2014 |
End | 04/2017 |
Description | EPSRC equip - seahorse |
Amount | £115,000 (GBP) |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2014 |
End | 03/2015 |
Description | EU - dave |
Amount | £300,000 (GBP) |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 08/2012 |
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 | Public |
Country | United Kingdom |
Start | 09/2013 |
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 | Public |
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 | Public |
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 | Public |
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 | 09/2015 |
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 | Public |
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 | Public |
Country | United Kingdom |
Start | 09/2015 |
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 | Public |
Country | United Kingdom |
Start | 04/2015 |
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 |
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 | Switzerland |
Sector | Private |
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 |