Transgenerational epigenetic inheritance: mechanisms and consequences for metabolism and ageing

Lead Research Organisation: Babraham Institute
Department Name: UNLISTED

Abstract

Epigenetic changes that occur during the lifetime of an individual are generally not inherited by the next generation, as this could subvert epigenetic reprogramming events needed to reinstate totipotency. Yet, some genomic elements remain incompletely reprogrammed, and may thus represent a key genomic vehicle for transgenerational epigenetic inheritance47. Transgenerational inheritance requires that the germline remembers exposure to environmental changes and allows for these to be inherited to the next generation(s). Nutritional stress can mediate transgenerational memory through histone marks and small RNA pathways in invertebrates and DNA methylation changes in mice48,49. As observed in many studies, the inheritance mediated by epigenetic modifications reverts back to wild-type after one or a few generations. However, some epigenetic changes can lead to more permanent genome rearrangements, when coupled to genomic instability. For example, nutritional stress can lead to instability of high copy number ribosomal DNA (rDNA), resulting in copy number variation (CNV) at rDNA loci. There are many key aspects that remain unresolved in the field and this Objective tackles two essential questions: firstly, what are the mechanisms by which epigenetic reprogramming normally returns cells to a naïve and totipotent stage and could these mechanisms thereby mediate transgenerational inheritance upon experimental manipulation. Secondly, can, and if so how could, stressors such as age and nutrition contribute to inheritance by modifying CNV through gametes with consequences for metabolism and ageing in subsequent generations.
 
Description Epigenetic changes that accumulate during the lifetime of an individual and that occur in response to the environment are usually erased by epigenetic reprogramming to reinstate pluripotency. However, some genomic elements remain incompletely reprogrammed and can be heritable for several generations. We have studied two examples of epigenetic inheritance. First, we observe that a high fat diet during gestation can result in the inheritance of addictive behaviors, obesity and insulin resistance in the progeny for up to 3 generations (PMID 30315171). Second, cold exposure of males before mating results in improved systemic metabolism and protection from diet induced obesity in male-offspring, which may be transmitted by an altered methylome in cold exposed sperm (PMID 29988127). As observed in many studies, the inheritance mediated by epigenetic modifications reverts back to wild-type after one or a few generations. However, some epigenetic changes can lead to more permanent genome rearrangements, when coupled to genomic instability. We have done this using yeast cells and learned that copy number of environmentally responsive genes can be induced in response to the environment (PMID: 28654659). We have determined rDNA copy number changes in ageing yeast (PMID:30274593) but observe no change in heritable chromosomal rDNA copy number but can be heritable as extrachromosomal DNA (manuscript in preparation).
Exploitation Route (1) We will work on repository sites which contains experimental details of the protocols that are in use for this proposal and those which represent high novelty, in order to share expertise with the scientific community (2) disseminate the results of our work and exchanges ideas with colleagues at national and international conferences. (3) We are seeking to identify partners to work with to exploit the outcomes of our research. This will be coordinated through the BI KE team and Babraham's wholly-owned trading arm, Babraham Commercialization Services (BCS), which promotes the commercialisation of results coming from the BI through filing and licensing patents and facilitating knowledge exchange with companies. (4) We are engaged in many events related to extending epigentic knowledge to the public (5) This awarded grant has made possible the training of postdocs and PhD Students as well as led to multiple national collaborations.
Sectors Communities and Social Services/Policy,Education,Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2001333
 
Description The Epigenetics ISP has been involved in several engagement activities with secondary degree students. For example, the Casanueva group obtained a Royal Society Partnership Grant in 2017, to introduce Colchester Highschool students to the use of model organisms to study ageing. Another example is that the Epigenetics ISP supported the Sophianum School in the Netherlands during 2017 and 2018. The Institute set challenge projects relating to the Institute's animal care facilities and Epigenetics to teams of secondary and sixth-form students as part of the national Dutch Technasium scheme. The collaboration won an Openness Award from Understanding Animal Research in December 2017.
First Year Of Impact 2017
Impact Types Cultural,Societal

 
Description Chair of SAB Centre for Trophoblast Research University of Cambridge
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Has changed the perception of placenta and trophoblast in reproduction
 
Description Flagship
Amount € 1,000,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 02/2019 
End 03/2020
 
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
 
Title C elegans Metabolic Reconstruction Model 
Description Merged and re-annotated C elegans Metabolic Reconstruction Model 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? Yes  
Impact This is a great improvement to the C elegans research community 
 
Title PCR Bayes 
Description Novel algorithm to quantify expression and biological variability of steady state transcripts 
Type Of Material Technology assay or reagent 
Year Produced 2017 
Provided To Others? No  
Impact This is a novel tool which extends the capabilities of C elegans researchers to quantitate biological noise in single worms 
 
Title Transcriptome datasets of reproductive tissues in ageing females (GSE98901) 
Description RNA-seq datasets of trophoblast, endometrium and deciduae of mouse conceptuses developed in young versus aged females 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Significant changes imposed by maternal age on expression profiles of endoemtrial tissue and decidual development. Work shows the impact of the older female on reproductive success, unrelated to oocyte fitness. 
 
Title copper response in yeast 
Description Response of yeast to copper treatment by RNAseq and replication fork stalling 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact data re-use 
URL https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE86283
 
Description CEGX 
Organisation Cambridge Epigenetix
PI Contribution Data generated by CASE PhD student as preliminary/pilot data for target validation of epigenetic changes in disease.
Collaborator Contribution Industrial CASE PhD studentship partner Cambridge Epigenetix (CEGX) provided help and advice in novel, proprietary technique and enabled student to perform this new method of epigenetic target validation during the placement period.
Impact PhD studentship in progress. Manuscript(s) will be generated from this work, possibly even targets for follow-on work and potential commercialisation as epigenetic biomarkers.
Start Year 2016
 
Description Christian Wolfrum - transgenerational epigenetic inheritance 
Organisation ETH Zurich
Department Institute of Food, Nutrition and Health
Country Switzerland 
Sector Public 
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 Deciduoma 
Organisation National Institute of Environmental Health Sciences
Department Reproductive and Developmental Biology Laboratory
Country United States 
Sector Public 
PI Contribution Characterisation of reproductive defects in older females
Collaborator Contribution Decidualisation model to assess the effect in the absence of an implanting embryo
Impact Collaborative publication (PMID: 28874785)
Start Year 2016
 
Description Development of computational methods for the quantification of biological variability 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR.
Collaborator Contribution Development of an algorithm based on Bayesian statistics that quantifies variability in steady state levels of mRNA from nanofluidics-based PCR.
Impact It is a multi-disciplinary collaboration involving high end PCR technology and statistical modelling.
Start Year 2015
 
Description Rakyan for mouse rDNA 
Organisation Queen Mary University of London
Department Blizard Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of mouse rDNA CNV assay
Collaborator Contribution Mouse models and project lead
Impact None yet...
Start Year 2016
 
Description Uterine pathologies and maternal age 
Organisation University of Edinburgh
Department MRC Centre for Reproductive Health
Country United Kingdom 
Sector Public 
PI Contribution Molecular assessment of changes occurring in older females
Collaborator Contribution Pathological characterisation and assessment of uterine pathologies that become more frequent with age
Impact Collaboration established. Application for future funding in progress.
Start Year 2017
 
Description single cell TSCs 
Organisation University of Cambridge
Department Department of Obstetrics & Gynaecology
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration with Prof Steve Charnock Jones to form core of Centre of Trophoblast Research single cell transcriptomics profiles of mouse (and human) trophoblast stem cells under various conditions, as well as of placentas. Provided cells and tissues and culture media components to collaborator.
Collaborator Contribution Set up Drop-seq and optimising technique for nuclear RNA sequencing, required for syncytia. Performed sc-RNA-seq.
Impact Manuscript in preparation.
Start Year 2017
 
Description Article on JH lab research on WIRED website and in Quanta magazine 
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 Article on JH lab research following in-depth interview
Year(s) Of Engagement Activity 2017
URL https://www.wired.com/story/bacteria-may-rig-their-dna-to-speed-up-evolution/
 
Description Babraham Schools day 2018 
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 Schools
Results and Impact Experiments on epigenetics for local 6th form schools
Year(s) Of Engagement Activity 2018
 
Description British Yeast Group meeting 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk to scientists in this and other areas focused on yeast research
Year(s) Of Engagement Activity 2017
URL https://microbiologysociety.org/event/society-events-and-meetings/focused-meeting-2017-british-yeast...
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock presented at the Cambridge Science Festival, involving activities and question/answer interactions with members of the public
Year(s) Of Engagement Activity 2018
 
Description Cold Spring Harbor Laboratory meeting: Stem Cell Biology, New York (USA) (VPG, CS) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Participation in confenrence, poster presentation by both post-doctoral reserachers involved in this activity (VPG and CS) and engagement in discussions and broadening of scientific horizon
Year(s) Of Engagement Activity 2017
 
Description EMBL Mammalian Genetics and Genomics Conference (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker at AMBL Conference Mammalian genetic and Genomic, Heidelberg, Germany
Year(s) Of Engagement Activity 2017
 
Description EU-Life meeting Principles of Homeostasis, Berlin (Germany) (VPG) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Participation and poster presentation at EU LIfe meeting "Principles of Homeostasis" held in Berlin, Germany (2017)
Year(s) Of Engagement Activity 2017
 
Description GENIE network of C elegans researchers 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Joining this pan european network has allowed us to attend conferences, network with other C elegans labs across Europe and obtaining funding to organise a workshop on C elegans metabolic reconstruction.
Year(s) Of Engagement Activity 2015,2016,2017,2018
 
Description GENiE workshop "Extending the consensus representation of C. elegans metabolism" 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
Year(s) Of Engagement Activity 2018
URL https://www.helmholtz-muenchen.de/genie-workshop-2017/program/index.html
 
Description Genetics Society and BSDB Spring Meeting, Warwick, UK (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited speaker at annual spring meeting of the Genetics Society and British Society for Developmental Biology (BSDB) in Warwick, UK (2017)
Year(s) Of Engagement Activity 2017
 
Description Genetics Society annual autumn meeting - poster presentation RS 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presentation of a poster with the newest data on this work. Meeting held in London, UK (2017).
Year(s) Of Engagement Activity 2017
 
Description IFPA Meeting, Manchester, UK (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk at IFPA Meeting held in Manchester, UK (2017)
Year(s) Of Engagement Activity 2017
 
Description ISSHP Meeting, Berlin, Germany (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited talk at ISSHP Meeting held in Berlin, Germany (2017)
Year(s) Of Engagement Activity 2017
 
Description Keynote speaker, CTR Anniversary Meeting, Cambridge, UK (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Keynote lecture at 10th Anniversary Meeting of the Centre for Trophoblast Research, University of Cambridge (2017)
Year(s) Of Engagement Activity 2017
 
Description Meeting organiser, Reproduction and Development, Cambridge 2018 (MH) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Co-organisation of meeting, Reproduction and Development, held in Cambridge, UK (2018).
Year(s) Of Engagement Activity 2018
 
Description Organisation of C.elegans Cambridge local area meetings 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact An audience of about 10-15 science labs from around the Cambridge area attend these events, including many PhD students and postdocs. The aim of these meetings is dissemination of techniques and science as well as networking.
Year(s) Of Engagement Activity 2015,2017,2018
 
Description Partcipation in The Future of Ageing 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact A representative of the Casanueva lab attended a debate on the future of gein at London School of Economics geared towards general public.
Year(s) Of Engagement Activity 2018
 
Description Podcast with Dr Kat Arney on the impact of placentation and maternal age on reproductive outcome 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Podcast as descibed above
Year(s) Of Engagement Activity 2017
 
Description Postgraduate course Epigenetics in Reproductive Biology, University of Murcia, Spain (VPG) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact Invited talk and workshop participation as part of postgraduate course on reproductive epigenetics
Year(s) Of Engagement Activity 2016,2017
 
Description Radio interview DeutschlandFunk 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Radio Interview for DeutschlandFunk on the impact of maternal age on pregnancy success, irrespective of the increased risk of defects in the egg
Year(s) Of Engagement Activity 2017
URL http://www.deutschlandfunk.de/alter-des-uterus-entscheidend-junges-glueck-in-jungen.676.de.html?dram...
 
Description Royal Society Summer Exhibition 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Babraham Institute exhibit on the Epigenetic Ageing Clock as invited entry presented at the Royal Society Summer Exhibition, involving activities and question/answer interactions with members of the public, fellows of the Royal Society, policymakers
Year(s) Of Engagement Activity 2018
 
Description Savile Club epigenetics talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Presentation about epigenetics at the London Savile Club
Year(s) Of Engagement Activity 2018
 
Description Sophianum School collaboration - Technasium 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact The Babraham Institute is continuing to coordinate activities supporting its commitment as a signatory of the Concordat on Openness on Animal Research. Institute staff, including animal unit managers, have been working closely with a school in the Netherlands to prepare and launch the Institute's contribution to the national 'Technasium' education programme, which aims to draw together students and industry.

Two projects, developed in collaboration with the Institute's Public Engagement team and teachers from the Sophianum School in Gulpen, will challenge students to research and design systems to improve the efficiency and safety of animal care systems. A third project will require the students to research how legislation regulating the use of animals in science, as well as public opinion, can vary throughout Europe and the world.

A two-day visit on 19th & 20th May will kick-start a 10-week programme for the 15-year old students, who will work in teams and compete to design the best solutions to the challenges. The Institute's animal technicians will monitor student progress by commenting on YouTube videos posted fortnightly by the teams. Regular video calls into the animal unit and the Institute's laboratories will allow live discussion between the students, the animal technicians and the scientists who use animals as part of their research.

The challenge projects will finish in July, with the winning Sophianum team coming to the Babraham Institute as part of their prize. The students will visit Institute animal facilities and will get a chance to see the award-winning camera system which displays live feeds from the facility - allowing groups to appreciate first-hand both the animal care environment and the nature of working within an animal research unit.

This pilot project will also involve sixth-form students at the school who will learn about the Institute's research and take part in workshops to discuss the ethics of the use of animals in science. The Institute has been running ethics workshops for secondary and sixth form students since 2005, with contributions from Understanding Animal Research, the European Animal Research Association and the Institute of Animal Technology.

The success of the Technasium project will be evaluated by both the Institute and Sophianum School, with a view to developing future challenges.
Year(s) Of Engagement Activity 2017,2018
 
Description Talk at British Yeast Group by Lab member Ryan Hull 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Conference presentation at the British Yeast Group meeting
Year(s) Of Engagement Activity 2018
 
Description Talk at Cambourne Library 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact 15 general audience attended an Epigenetics presentation and discussion
Year(s) Of Engagement Activity 2018
 
Description Talk at DNA Replication as a Source of DNA Damage Conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk to other members of research community.
Year(s) Of Engagement Activity 2017
URL https://www.fusion-conferences.com/conference67.php
 
Description Talk at EMBO Evolution and Ecology meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk and poster presentation at EMBO meeting
Year(s) Of Engagement Activity 2018
URL https://www.embl.de/training/events/2018/EAE18-01/
 
Description Talk at EpiChrom 2019 by lab member Ryan Hull 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Talk at EpiChrom 2019 meeting
Year(s) Of Engagement Activity 2019
URL https://www.scilifelab.se/epichrom-2019/
 
Description The Ageing Cell Conference, Cambridge, UK (MH) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Invited talk at The Ageing Cell Conference held in Cambridge, UK (2017)
Year(s) Of Engagement Activity 2017
 
Description UKRI launch 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact UKRI launch event 2018
Year(s) Of Engagement Activity 2018