The hundreds of cell types in our bodies differ from each other because they turn different sets of genes on and off. Super-enhancers are key switches in the genome, in-between the genes, that turn certain genes on. Which super-enhancers are active in a particular cell has a big effect on what type of cell it is. Super-enhancers don’t always control the genes that are nearby in the genome though. In fact, as the DNA is physically looped inside a cell, super-enhancers can affect genes that are a long way away in the genome.
Writing in Cell Reports, Dr Clara Novo, Dr Peter Rugg-Gunn and colleagues in the Fraser lab at the Babraham Institute, examined super-enhancers in embryonic stem cells (ESCs) from mice using a technique called promoter-capture Hi-C (PCHi-C). This approach allows scientists to examine which genes are physically in contact with – and therefore might be controlled by – super-enhancers. This has led to the discovery of many new targets of super-enhancers and shown that super-enhancers can contact several genes. Since previous methods could only show links between single super-enhancers and single genes over short-distances, this reveals a new level of complexity in how super-enhancers work.
The results also reveal that super-enhancer contacts change when ESCs prime towards differentiation – the process by which stem cells specialise to become different types of cells. In particular, the more specialised epiblast-derived stem cells (EpiSCs) have fewer long-range contacts between super-enhancers and genes than ESCs. The experiments reveal that a protein called NANOG in ESCs enables some of these long-range connections, which are lost during the transition to EpiSCs. Overall, this suggests that, as stem cells specialise into different cell types, there are large changes in how the genome is regulated.
Super-enhancers play key roles in a range of diseases at different stages of life. Understanding how they work and the effects of trying to control them is vital to finding new ways to safely treat and manage different illnesses. The discovery that individual super-enhancers can control several genes and act over long distances highlights the importance of this work in unpicking the complexity of these gene control networks.
Find out more about our epigenetic research in ageing at our Cambridge Science Festival event on 17th March 2018 and at the Royal Society Summer Science Exhibition in July.
For more research from the Rugg-Gunn group and colleagues see here.
Novo, C.L., Javierre, B-M., Cairns, J., Segonds-Pichon, A., Wingett, S.W., Freire-Pritchett, P., Furlan-Magaril, M., Schoenfelder, S., Fraser, P., Rugg-Gunn, P.J., Long-range enhancer interactions are prevalent in mouse embryonic stem cells and are reorganized upon pluripotent state transition. Cell Reports, 2018, 22 (10) 2615 - 2627
Work at the Babraham Institute is possible thanks to the Biotechnology and Biological Sciences Research Council, in particular this research relates to the Strategic Programme Grant for Epigenetics. This work was also supported by the Wellcome Trust, the European Comission Network of Excellence EpiGeneSys and the Medical Research Council.
Top: Graphical representation of DNA bending in different types of cells (ESCs and EpiSCs). The straight line represents positions along a piece of DNA while the curved lines indicate where two regions of the DNA are physically close together in each cell type. Differences between the upper and lower halves of the figure indicate genome rearrangements between ESCs and EpiSCs. Image Credit: Novo et al.
Inset: Graphic representing physically how a piece of DNA might be arranged inside a cell and how this may change as a cell transitions from one cell type to another. Image credit: Novo et al.
Affiliated Authors (in author order)
Clara Novo - Epigenetics Laboratory, The Babraham Institute
Biola-Maria Javierre, Jonathan Cairns, Paula Freire-Pritchett, Mayra Furlan-Magaril, Stefan Schoenfelder - Nuclear Dynamics Laboratory, The Babraham Institute
Anne Segonds-Pichon. Steven Wingett - Bioinformatics Facility, The Babraham Institute
Peter Fraser - Group Leader, Nuclear Dynamics, The Babraham Institute
Peter Rugg-Gunn - Group Leader, Epigenetics Laboratory, The Babraham Institute
About the Babraham Institute
The Babraham Institute receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) to undertake world-class life sciences research. Its goal is to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Research focuses on 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.
06 March 2018