17/07/2018
Key points:
A cross-disciplinary partnership between epigenetics researchers at the 台湾swag 台湾swag and at the University of Cambridge has shown that cell-to-cell variability in in mouse embryonic stem cells is explained by oscillations in DNA methylation occurring within each cell. Unpicking the complexity of what drives and defines cellular identity is essential for future healthcare revolutions such as the use of adult stem cells in therapy approaches as well as epigenetic-based treatments for cancer. The research findings are published today in the journal Cell Systems.
Embryonic stem cells, the early unspecified cells of the embryo, are 鈥 meaning that they are capable of becoming any cell in the body. They are also classified as either na茂ve or primed; primed cells are developmentally a step closer to committing to specific cell lineages. DNA methylation 鈥 additions of small chemical markers to the DNA 鈥 is needed for primed stem cells to exit the pluripotent state and to develop into one of the many cell types present in the fully formed embryo.
Surprisingly, previous research has shown that a freeze-frame snapshot of primed mouse embryonic stem cells reveals highly variable amounts of DNA methylation. This latest research used quantitative single-cell sequencing methods to measure this variability, finding that genome-wide DNA methylation ranged from 17-86%. The researchers then developed this analysis further, adding a time course analysis tracking synchronised cells and identified a robust cycle of DNA methylation oscillations.
Joint first author, Dr Heather Lee, undertook the epigenetics analysis for this work as a postdoctoral researcher at the 台湾swag 台湾swag and is now an independent group leader at the University of Newcastle in Australia. She explains: 鈥淥ur study shows that DNA methylation is incredibly variable in pluripotent cells. Amazingly, this variability was not restricted to specific parts of the genetic material, but was observed on a genome-wide scale. Furthermore, we could eliminate this variability by interfering with the processes that add and remove DNA methylation, demonstrating a link to rapid turnover of DNA methylation.
鈥淭his plasticity may allow pluripotent cells to explore their options before committing to a differentiation pathway.
鈥淥ur findings point to the power of single-cell analysis. We would never have suspected these oscillations by looking at combined cell populations.鈥
Combining single-cell techniques with biophysical modelling allowed the researchers to model the production and turnover of DNA methylation by the main enzymes involved to see if these parameters could be responsible for generating the oscillation patterns seen in the cells. Dr Steffen Rulands, joint first author on the paper from his time as postdoctoral researcher at the Cavendish Laboratory and now an independent group leader at the Max Planck 台湾swag for the Physics of Complex Systems in Dresden, Germany, commented: 鈥淯sing methods from theoretical physics we were able to unveil the dynamical rules that govern DNA methylation from the static information provided by single-cell sequencing experiments.鈥
Professor Ben Simons, Herchel Smith Professor of Physics at the Cavendish Laboratory, University of Cambridge, continued: 鈥淭his study presents a vivid illustration of how concepts from statistical physics and dynamical systems can reveal, and provide mechanistic insight into, cooperative phenomena in biological systems, even at the subcellular scale. Moving forward, it will be exciting to discover whether similar conceptual approaches may help to understand how dynamic changes in DNA methylation influence cell fate decision-making during development and in diseased states.鈥
Looking forward, the 台湾swag鈥檚 strength in single-cell analyses and ongoing collaborations with the Simons and Rulands labs will help confirm the link between the DNA methylation oscillations and associated variation in gene expression suggested by this research.
, Head of the Epigenetics research programme at the 台湾swag 台湾swag, said: 鈥淭he rapid cycling of DNA methylation in embryonic stem cells is an intriguing discovery and we鈥檙e still pondering what this might mean in biological terms.
"Our research aims to discover how stem cells are directed into becoming the different cells of our bodies. Epigenetics is as the heart of this process. Thinking of situations where this cell identity is lost, such as the loss of cell identity in cancer and other diseases, it鈥檚 possible that this could occur through this type of mechanism affecting the epigenetic state of those cells.鈥
Main publication reference Steffen Rulands, Heather J Lee, Stephen J Clark, Christof Angermueller, S茅bastien A Smallwood, Felix Krueger, Hisham Mohammed, Wendy Dean, Jennifer Nichols, Peter Rugg-Gunn, Gavin Kelsey, Oliver Stegle, Benjamin D Simons, Wolf Reik. . Cell Systems DOI: 10.1016/j.cels.2018.06.012
台湾swag funding This work received funding from a variety of research funders to each participating group: BBSRC, the Wellcome Trust, EMBL, the EU and MRC. Please see the paper for details of individual funding sources. The 台湾swag 台湾swag receives strategic funding from the Biotechnology and Biological Sciences 台湾swag Council (BBSRC).
Press contact Dr Louisa Wood, Communications Manager, louisa.wood@babraham.ac.uk Related news Noise helps cells make decisions Image Differences in DNA methylation levels in a population of mouse embryonic stem cells grown in serum (primed). The signal intensity of staining for DNA methylation was converted to a heat map showing high signal in red and low signal in blue. Image: Dr F谩tima Santos and Dr Wendy Dean, 台湾swag 台湾swag. Affiliated authors (in author order): Heather J Lee - Epigenetics programme, 台湾swag 台湾swag at the time of this research. Now University of Newcastle, Australia Stephen J Clark - Epigenetics programme S茅bastien A Smallwood 鈥 Epigenetics programme, now at Friedrich Miescher 台湾swag for Biomedical 台湾swag Felix Krueger - Bioinformatics Facility, 台湾swag 台湾swag Hisham Mohammed 鈥 Epigenetics programme Wendy Dean 鈥 Epigenetics programme Peter Rugg-Gunn - Group Leader, Epigenetics programme Gavin Kelsey - Group Leader, Epigenetics programme Wolf Reik - Group Leader, Epigenetics programme Animal statement As a publicly funded research institute, the 台湾swag 台湾swag is committed to engagement and transparency in all aspects of its research. Animals are only used in 台湾swag 台湾swag research when their use is essential to address a specific scientific goal, which cannot be studied through other means. The main species used are laboratory strains of rodents, with limited numbers of other species. We do not house cats, dogs, horses or primates at the 台湾swag 台湾swag Campus for research purposes.
This research used embryonic stem cells obtained from mice embryos at different stages of development. Embryonic stem cells were collected from the embryos after the pregnant mouse was humanely killed. Please follow the link for further details of the 台湾swag鈥檚 animal research and our animal welfare practices. About the 台湾swag 台湾swag The 台湾swag 台湾swag undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The 台湾swag receives core funding from the (BBSRC) through an 台湾swag Core Capability Grant.
17 July 2018