Epigenetic reprogramming in mammalian development

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

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.

Publications

10 25 50
 
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.
First Year Of Impact 2012
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Description EU NoE EpiGeneSys
Amount £400,000 (GBP)
Funding ID 257082 
Organisation European Commission 
Sector Public
Country European Union (EU)
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 08/2019 
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 10/2018 
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 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
 
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 MRC EASIH 
Organisation University of Cambridge
Department Cambridge Institute for Medical Research (CIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution increased opportunities for deep sequencing using alternative platforms such as Roche 454 and ABI Solid
Collaborator Contribution MRC East Anglia Sequencing and Informatics Hub established in 2009
Impact see above
Start Year 2009
 
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 Role of Np95 in epigenetic reprogramming 
Organisation RIKEN
Country Japan 
Sector Public 
PI Contribution We are analysing the effects of Np95 deletion in zygotes and early embryos
Collaborator Contribution Contribution of unpublished conditional knockout in the key epigenetic regulator Np95
Impact The first results have been obtained and look quite interesting
Start Year 2008
 
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 Sanger Single Cell Genomics Centre 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Helped to establish the Single Cell Genomics Centre at Sanger/EBI
Collaborator Contribution A number of Sanger and EBI PIs were involved
Impact Genomics, transcriptomics, epigenomics, computational biology
Start Year 2013
 
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