Epigenetic reprogramming in mammalian development
Lead Research Organisation:
Babraham Institute
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The human genome sequence provides insights into human diseases and how certain characteristics are inherited in families. However the main causative factors for many common human diseases remain unknown. As an organism develops, the genome is regulated such that different genes function in different tissues and organs of the body. This is brought about, at least in part, by epigenetic information in the genome in the form of chemical modifications of the DNA and of proteins that are intimately associated with DNA. This is known as the epigenome, and different organs in the body have different epigenomes (while they have the same genome) which are important for their function. Once the organs have formed, the epigenome is normally stable, but in germ cells and early embryos, the epigenome becomes reprogrammed on a large scale. We are trying to find out how the epigenome becomes reprogrammed, and if reprogramming goes wrong, whether this can result in faulty development and diseases. Understanding epigenetic reprogramming is also important in order to harness the promise of stem cells for novel therapies of human diseases.
Planned Impact
unavailable
Organisations
- Babraham Institute (Lead Research Organisation)
- Merck (Collaboration)
- University of Copenhagen (Collaboration)
- University of Stuttgart (Collaboration)
- University of Dundee (Collaboration)
- Max Planck Society (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- EMBL European Bioinformatics Institute (EMBL - EBI) (Collaboration)
- ETH Zurich (Collaboration)
- University of Oxford (Collaboration)
- University of Cantabria (Collaboration)
- Cambridge Epigenetix (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
People |
ORCID iD |
| Wolf Reik (Principal Investigator) |
Publications
Linker SM
(2019)
Combined single-cell profiling of expression and DNA methylation reveals splicing regulation and heterogeneity.
in Genome biology
Messmer T
(2019)
Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution
in Cell Reports
Milagre I
(2017)
Gender Differences in Global but Not Targeted Demethylation in iPSC Reprogramming.
in Cell reports
Montalbán-Loro R
(2019)
TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn.
in Nature communications
Oda M
(2013)
Regulation of Lineage Specific DNA Hypomethylation in Mouse Trophectoderm
in PLoS ONE
Parry A
(2021)
Active turnover of DNA methylation during cell fate decisions.
in Nature reviews. Genetics
Patalano S
(2015)
Molecular signatures of plastic phenotypes in two eusocial insect species with simple societies.
in Proceedings of the National Academy of Sciences of the United States of America
Peat JR
(2014)
Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation.
in Cell reports
Raiber EA
(2018)
5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells.
in Nature chemistry
Reik W
(2014)
Epigenetics: Cellular memory erased in human embryos.
in Nature
| Description | Lay The genome consists of DNA but there are also chemical modifications to the genome or to proteins which wrap around the genome, and thus provide 'epigenetic' marks that are important for genome function. For example, during embryo development, different cell types emerge that carry the same genome but have different epigenetic marks associated with the DNA. These different 'epigenomes' together with transcription factors (proteins that bind to DNA and interpret the DNA code) help cells to become different from each other (kidney or brain cells, for example) and then to retain their identity (as kidney or brain). However when germ cells (egg or sperm) are formed for reproduction and the next generation, these acquired epigenetic marks need to be removed from the DNA again. We discovered a powerful mechanism by which marks are removed and the slate is wiped clean again. This is important for embryo cells to start development afresh, and our insights are therefore useful for devising better protocols for the use of embryo stem cells for therapy. Our work also suggests that life or nutritional experiences our grandparents were exposed to will not normally be passed on to ourselves. We have also developed new technologies for reading out epigenetic marks in our genome, including in single cells. Those methods have utility in early and precise diagnosis of certain cancer types. Specialist Work in this grant follows on from our discovery that whilst epigenetic modifications are largely stable in somatic cells in an adult organism, there is genome-wide erasure of epigenetic information in early embryos and in primordial germ cells. We found that global epigenetic reprogramming, which is conserved in mammals, is linked with naïve pluripotency and may explain the relative scarcity of transgenerational epigenetic inheritance in mammals. We also discovered the major molecular mechanisms of global reprogramming, including mechanisms of active and passive demethylation. We have recently found links between global reprogramming and transposon control in the germline, and with zygotic genome activation, respectively. We were first to apply whole genome bisulfite sequencing to genome-wide epigenetic reprogramming in the germ line. We subsequently invented new methods for sequencing of hydroxymethylation and formylcytosine, discovering modifications of regulatory elements such as enhancers during development. We developed the first method for whole genome methylome sequencing in single cells, and discovered profound epigenetic heterogeneity in early embryos particularly in enhancers which suggests that such heterogeneity may underlie cell fate decisions and symmetry breaking during development. We have recently developed multi-omics single cell methods such as those that connect epigenetic marks with the transcriptome, together with computational and statistical methods for their analysis. |
| Exploitation Route | For our discovery of the mechanisms of epigenetic reprogramming in early embryos and germ cells, this provides an explanation for why transgenerational epigenetic inheritance is so relatively rare in mammals; that's because most of the epigenetic marks acquired during our lifetime are erased in the germ line. It's an important message to health services and policy providers because it is relatively unlikely that environmental and nutritional influences on our grandparents and parents have a major impact on our health. Our discovery of reprogramming mechanisms to naïve pluripotency has resulted in a patent application with the potential of developing better stem cells in humans. For the new sequencing technologies we have developed this has resulted in the founding of the company Cambridge Epigenetix which deals with the applications of new epigenetic sequencing technologies to cancer diagnosis. Our single cell multi-omics technologies are contributing to the Human Cell Atlas, the Human Developmental Biology Initiative, and EU LifeTime. |
| Sectors | Environment Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | The findings under this award have led to the establishment of the company Cambridge Epigenetix in 2012 on the Babraham campus based on the development of oxidative bisulfite sequencing. In a recent funding round the company has raised close to £100M in investment. In the longer term fundamental discoveries made under this award on epigenetic reprogramming led to the realisation that epigenetic changes acquired during ageing can be reversed using rejuvenation programming and these insights in the field to which we contributed led to the establishment of Altos Labs, a start-up company in the US and UK with £3B of funding and a new research institute in Cambridge. |
| Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Economic |
| Description | ERC Advanced grant |
| Amount | £2,200,000 (GBP) |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 01/2021 |
| End | 12/2026 |
| Description | EU NoE EpiGeneSys |
| Amount | £400,000 (GBP) |
| Funding ID | 257082 |
| Organisation | European Commission |
| Sector | Public |
| Country | Belgium |
| Start | |
| Description | Enhancer DNA methylation dynamics during early mammalian development |
| Amount | £300,000 (GBP) |
| Funding ID | 215912/Z/19/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 07/2019 |
| End | 08/2023 |
| Description | Investigator Award |
| Amount | £2,600,000 (GBP) |
| Funding ID | 210754/Z/18/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2018 |
| End | 09/2023 |
| Description | MRC Collaboration Grant (deep sequencing in Epigenomics) |
| Amount | £960,000 (GBP) |
| Funding ID | G0801156 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | Special initiative |
| Amount | £10,000,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2019 |
| End | 04/2024 |
| Description | Wellcome Trust Strategic Award |
| Amount | £2,400,000 (GBP) |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2019 |
| Description | Wellcome collaborative award in science |
| Amount | £3,900,000 (GBP) |
| Funding ID | 220379/z/20/z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 12/2020 |
| End | 11/2025 |
| Title | Single cell multi-omics (scNMT-seq) |
| Description | Single cell triple-omics which records the transcriptome, methylome, and chromatin accessibility from the same single cell |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2018 |
| Provided To Others? | Yes |
| Impact | This method was applied to the first real biology question in 2019 on an investigation of mouse gastrulation (Argelaguet et al 2019 Nature). The joint first author Stephen Clark was awarded the researcher of the year award 2019 by the Cambridge Independent newspaper. |
| Title | Single cell triple-omics |
| Description | Single cell triple-omics combining transcriptome, methylome, and chromatin accessibility from the same single cell. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | This method was just published. |
| Description | Austin Smith |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Epigenomics and multi-omics sequencing |
| Collaborator Contribution | Human and mouse pluripotent stem cells |
| Impact | Several collaborative publications. |
| Start Year | 2013 |
| Description | Christian Wolfrum - transgenerational epigenetic inheritance |
| Organisation | ETH Zurich |
| Department | Institute of Food, Nutrition and Health |
| Country | Switzerland |
| Sector | Academic/University |
| PI Contribution | Carried out transcriptome and methylome analysis of transgenerational epigenetic models |
| Collaborator Contribution | Provided transgenerational epigenetic mouse models of high fat diet and cold shock |
| Impact | Behavioural studies, nutrition, epigenetics, epigenomics, transcription |
| Start Year | 2016 |
| Description | Collaboration with Alvaro Rada-Iglesias |
| Organisation | University of Cantabria |
| Country | Spain |
| Sector | Academic/University |
| PI Contribution | Single cell multi-omics |
| Collaborator Contribution | In vitro PGCLC model |
| Impact | First datasets have been obtained. A training visit has taken place. |
| Start Year | 2019 |
| Description | Collaboration with Oliver Stegle |
| Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We conceived the study and provided sequencing datasets and interpretation. |
| Collaborator Contribution | They helped with conceiving the study and provided computational analysis and modelling. |
| Impact | Initial work has been published in Stubbs et al 2017. The work is multidisciplinary involving epigeneticists and computational biologists and modellers. |
| Start Year | 2016 |
| Description | Consultancy Cambridge Epigenetix |
| Organisation | Cambridge Epigenetix |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | I am a consultant for the company |
| Collaborator Contribution | None at present |
| Impact | Oxidative bisulfite sequencing |
| Start Year | 2012 |
| Description | Donal O'Carrol |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Helped with methylome sequencing and computational work. |
| Collaborator Contribution | Conceived and conducted the study. |
| Impact | Publication Vasiliauskaite et al 2017. Developmental biologists, epigeneticists, computational biologists. |
| Start Year | 2016 |
| Description | Gastrulation team |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Conceived of the project and lead partner. Contributing single cell multi-omics and embryology. |
| Collaborator Contribution | Helped to conceive of the project and several experimental and computational contributions. |
| Impact | First publication Mohammed et al 2017. Experimental embryology, single cell biology, computation, modelling, epigenetics. |
| Start Year | 2014 |
| Description | Greg Findlay - Biochemistry of DNMT1 and UHRF1 and demethylation |
| Organisation | University of Dundee |
| Department | National Centre for Protein Kinase Profiling |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have purified proteins and sent them to Greg Findlay's lab for proteomics and phosphoproteomics |
| Collaborator Contribution | They have identified several phosporylation sites of interest |
| Impact | Biochemistry, genetics, epigenetics, developmental biology |
| Start Year | 2018 |
| Description | Jenny Nichols mouse and human embryology |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Single cell multi-omics, mutants of epigenetic regulators. |
| Collaborator Contribution | Mouse and human embryos |
| Impact | Several collaborative publications and two joint grants. Multi-disciplinary between epigenetics, multi-omics, embryology, stem cell research. |
| Start Year | 2014 |
| Description | Jenny Nichols, Austin Smith |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Contributed to conceiving studies. Epigenetic profiling and analysis. |
| Collaborator Contribution | Conceived and conducted studies. |
| Impact | Publications Kalkan et al 2017, Guo et al 2017. Involves embryologists, stem cell biologists, computational biologists, epigeneticists. |
| Start Year | 2016 |
| Description | John Marioni |
| Organisation | EMBL European Bioinformatics Institute (EMBL - EBI) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Development of single cell multi-omics and application in several biological systems including mouse and human embryos and pluripotent stem cells. |
| Collaborator Contribution | Development of computational methods for single cell multi-omics. |
| Impact | Several collaborative publications and a joint grant. Multi-disciplinary between wet and dry lab multi-omics approaches. |
| Start Year | 2013 |
| Description | Jurkowski |
| Organisation | University of Stuttgart |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Helped with reagents and interpretation. |
| Collaborator Contribution | Conceived and conducted study. |
| Impact | Publication Stepper et al 2017. Involves biochemists, epigeneticists. |
| Start Year | 2016 |
| Description | Millipore DNA modification antibodies |
| Organisation | Merck |
| Department | MilliporeSigma |
| Country | United States |
| Sector | Private |
| PI Contribution | Commercialisation of DNA modification antibodies we have made |
| Collaborator Contribution | Commercialisation of DNA modification antibodies we have made |
| Impact | DNA modification antibodies |
| Start Year | 2011 |
| Description | Neil Brockdorff - X chromosome inactivation |
| Organisation | University of Oxford |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We helped with DNA methylome sequencing and analysis |
| Collaborator Contribution | Contributed relevant samples for sequencing |
| Impact | See publications. Biochemistry, cell biology, epigenomics, computational biology. |
| Start Year | 2016 |
| Description | Romain Barres |
| Organisation | University of Copenhagen |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | Single cell multi-omics |
| Collaborator Contribution | Human sperm from obese and control subjects |
| Impact | Several datasets. Multi-disciplinary between epigenetics, multi-omics, human cohorts. |
| Start Year | 2016 |
| Description | Steffen Rulands |
| Organisation | Max Planck Society |
| Department | Max Planck Institute for the Physics of Complex Systems |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | Single cell multi-omics datasets |
| Collaborator Contribution | Modelling approaches for single cell multi-omics datasets |
| Impact | One collaborative publication. Multi-disciplinary between biology and theoretical physics. |
| Start Year | 2015 |
| Description | Thorsten Boroviak - single cell multi-omics of primate development |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Carrying out single cell multi-omics on samples from non-human primates |
| Collaborator Contribution | Providing samples from non-human primates |
| Impact | See publications. Developmental biology, epigenomics, computational biology. |
| Start Year | 2017 |
| Description | Cheltenham Science Festival |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Keynote/Invited Speaker |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | A panel discussion and public debate on epigenetics at the Cheltenham Science Festival 2013 Several enquiries from members of the public who attended |
| Year(s) Of Engagement Activity | 2013 |
| URL | http://www.cheltenhamfestivals.com/science/whats-on/2013/flexible-inheritance-epigenetic-effects-on-... |
| Description | Royal Society Summer Exhibition 2012 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | Yes |
| Type Of Presentation | Workshop Facilitator |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Large public audience attendance over one week of all day exhibition Much positive feedback from members of the public and scientists attending |
| Year(s) Of Engagement Activity | 2012 |