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2018 Babraham Institute Annual Research Report Epigenetics 330-41 Epigenetics Inside cells, genetic information stored in DNA is packaged by proteins into a structure called chromatin. Epigenetics is the study of chemical modifications to DNA and to chromatin and the effects that these modifications have on genome function. Epigenetic marks are involved in the creation of different types of cells from stem cells and epigenetic changes over time are associated with ageing. Epigenetic marks also provide a form of cellular memory, recording certain information about past events and potentially carrying it between parent and child. Our work in this area aims to enhance our understanding of how epigenetics shapes human development and affects healthy ageing by examining: n How stem cells develop into different types of cells n How subtle epigenetic differences influence cell diversity n The impacts of diet on epigenetics, health and ageing n The inheritance of epigenetic memory between generations n How life events affect biological ageing through the epigenetic clock n New approaches and technologies to drive further progress 30 Group leaders Wolf Olivia Myriam Jon Gavin Peter Stefan Reik Casanueva Hemberger Houseley Kelsey Rugg-Gunn Schoenfelder 31 Epigenetics Single-cell epigenome landscape of development and ageing We are interested in epigenetic single cell. Our collaborators have mechanisms in mammalian developed computational methods Selected Impact Activities development and ageing. Epigenetic by which biologically meaningful n Members of the group formed Wolf Reik marks are able to regulate gene relationships between the regulatory a core part in developing and Programme leader expression and can behave as a form layers can be identified. In cells that delivering the Institute’s exhibit: of memory that records the history of exit from pluripotency and prepare for Race Against the Ageing Clock at Group members a cell. These marks include chemical differentiation, we made the surprising the 2018 Royal Society Summer Senior research scientists: changes to DNA or DNA-associated observation that cells become hugely Science Exhibition. Stephen Clark proteins. We are particularly interested heterogeneous in their methylation n Wolf Reik was featured in an Wendy Dean in the epigenetic rules that govern cell patterns especially in enhancers, and this article on big data ‘How big data is Melanie Eckersley-Maslin fate decisions in early development, and may be associated with transcriptional Fatima Santos changing science’ for the Wellcome how cell fate degrades during ageing. heterogeneity (or noise) which may help Ferdinand Von Meyenn Trust’s Mosaic platform, which Our research uses single-cell sequencing with cell fate decisions. We are also aiming (Left in 2018) was subsequently featured in methods to investigate cell fate to connect epigenetic marks in enhancers Research fellow: the Independent online on 11th decisions at the level of individual cells. with histone dynamics which may be Carine Stapel November, reaching over 22M (Started 2018) important for dynamic gene regulation. Current Aims people. Postdoctoral researchers: The group’s research focuses on Irina Abnizova n A visiting employee from Shift understanding how cell fate decisions are Rebecca Berrens (Left in 2018) Biosciences has been based in our Poppy Gould (Left in 2018) first programmed or primed, and which lab over the past year to apply Irene Hernando Herraez epigenetic layers this involves. We would the lab’s epigenetic ageing clock Nelly Olova then like to know which cell signalling- model to drug discovery. Aled Parry (Started in 2018) induced epigenetic rearrangements Solenn Patalano occur during fate change. Finally, we are PhD students: exploring whether epigenetic memory Celia Alda keeps cell identity of fully differentiated Diljeet Gill Oana Kubinyecz cells intact for the rest of our lives (or at (Started in 2018) least until we start to age). We are also Georgia Lea working on identifying DNA binding Tim Lohoff proteins which are involved in epigenetic Juliette Pearce priming of enhancers or promoters for Julia Spindel future lineage-specific gene expression. Research assistant: Mouse embryonic stem cells (ESCs) stained for DNA Laura Benson Progress in 2018 methylation, and pseudo-coloured according to (Started in 2018) In order to address these questions we signal intensity (higher signal - red; lowest - blue), Visiting scientists: are developing single-cell multi-omics revealing the heterogeneity of this epigenetic mark. Romina Durigon sequencing approaches which can reveal (Started in 2018) molecular hierarchies involved in fate decision-making. Our most advanced method combines sequencing of the transcriptome, the methylome, and chromatin accessibility from the same Publications www.babraham.ac.uk/our-research/epigenetics/wolf-reik @ReikLab n Rulands, S. et al. (2018) Genome-scale oscillations in DNA methylation during exit from pluripotency. Cell Syst. 7(1):63-76 n Clark, S.J. et al. (2018) scNMT-seq enables joint profiling of chromatin accessibility DNA methylation and transcription in single cells. Nat. Commun. 9(1):781 n Raiber, E.A. et al. (2018) 5-Formylcytosine organizes nucleosomes and forms Schiff base interactions with histones in mouse embryonic stem cells. Nat. Chem. 10:1258-1266 32 Understanding the interplay between stress and metabolism during early stages of ageing The discovery that genes control 2. How lipid and energy metabolism longevity has been quite significant for interplay with signalling pathways that the understanding of ageing because mediate healthy ageing. Metabolism is Olivia Casanueva it changed the view from a gradual a key mediator of longevity, however stochastic process, to a genetically its complexity makes it difficult to Group members controlled process that we can interfere study within the particular context Senior research assistant: with and potentially slow down. Since of ageing. With this goal in mind, we Sharlene Murdoch then, thousands of genes and conditions have developed computational tools to have been found to influence lifespan, Postdoctoral research study metabolic fluxes during ageing. with many of them controlling the way scientists: Progress in 2018 in which organisms deal with external Laetitia Chauve n We launched WormJam, a community- Cheryl Li (Left 2018) challenges brought by stress and driven platform that improved the Celia Raimondi nutrition. Such findings underscore the status of the existing model of C. elegans Boo Virk (Left 2018) key interplay between genes and the C. elegans worms labelled with a fluorescent protein by reconciling and manually curating environment and may explain the high and imaged using a confocal microscope. C. elegans PhD students: its metabolic pathways into a single Janna Hastings degree of discordance among identical is a really useful system for our research because we consensus model (refs 1 & 3). Abraham Mains (Left 2018) twins. Our lab’s interest is to understand can monitor fluorescent reporters of gene expression in vivo and study inter-individual variability in stress Manusnan Suriyalaksh the non-genetic influences on lifespan n We also discussed the relevance of response gene expression in isogenic individuals. Research assistants: and stress related phenotypes using these approaches in Current Opinions Francesca Hodge genetically identical lab strains of in Systems Biology (Hastings, in print), Sheikh Mukhtar C.elegans as a model organism. pointing at one of the key challenges Selected Impact Activities that we face when studying ageing with n The group was involved in several Visiting students: Current Aims these tools, namely that the modelling public engagement events Fatemeh Masoudzadeh Our overarching aim is to understand the tools available are optimised for throughout 2018, including being Pia Todtenhaupt (Left in 2018) molecular details of ageing and to discover animals or cells that are in the process part of the team that developed new ways to slow or even reverse the Other visitors: of growing, which is not happening in and presented the Institute’s Rebecca Aldunate ageing process. With that goal in mind, we aged animals. ‘Race Against the Ageing Clock’ (Left in 2018) use C. elegans to understand: exhibit at the Royal Society Rob Jelier (Left in 2018) n Confronted with this challenge, we 1. The significance of non-genetically Summer Exhibition, and sharing re-optimised the modelling tool by encoded variability in the expression the Institute’s science at the driving information from multi-omic of genes that respond to external cues Cambridge Science Festival and sources (both transcriptomics and such as temperature and nutrients. We events held as part of the LifeLab metabolomics) and were able to are interesting in finding how early project for European Researchers’ optimise this tool to study metabolic molecular differences in the way worms Night. fluxes during ageing (2). This re- respond to stress can influence and be optimisation represents a significant n Lab members were involved in predictive of lifespan. technical advance for the field and will organising the second EU-LIFE allow more accurate predictions of postdoc retreat. metabolic fluxes during the course of n The lab coordinates the ageing. organisation of local area Cambridge worm meetings. Publications www.babraham.ac.uk/our-research/epigenetics/olivia-casanueva n Witting, M. et al. (2018) Modeling meets metabolomics - The WormJam consensus model as basis for metabolic
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