Researchers at the Babraham Institute have discovered a strong physical gene interaction network that is responsible for holding genes in a silencing grip during early development. In the same way that people can interact with others in close proximity, say within the same room, or others millions of miles apart, there are also short- and long-range interactions within the genome forming a three-dimensional configuration where different parts of the genome come into contact with each other. The research, reported online in Nature Genetics, presents how key decision-making genes which specify the embryo’s blueprint for subsequent development are physically clustered in the nucleus of embryonic stem cells and maintained in a silent state.
The different cell types forming an embryo are derived from embryonic stem cells (ESCs). These cells are self-renewing and are maintained in an undifferentiated state meaning that they have the potential to become any cell type in the body. To become a specific cell type, embryonic stem cells progress along a developmental pathway, losing their stem cell characteristics and gaining new features. At a genomic level, assuming a specialised cellular identity reflects the switching on of appropriate developmental genes. Conversely, maintaining a stem cell identity requires the repression of developmental genes.
Using a novel technique developed at the Babraham Institute (Promoter Capture Hi-C), the researchers identified an unusually strong 3D network of developmental genes in ESCs. These genes encode proteins that establish the embryo’s body plan and direct organ development. As an ESC, you don’t want these instructions being read at this stage and so to prevent this, the genes are clustered together and silenced. The research showed that at the heart of this repression is a protein complex called Polycomb repressive complex (PRC1), a master regulator of ESC genome architecture. The research therefore establishes a mechanism, acting by physical interaction between specific genes and PRC1, which effectively holds genes in a silenced state. This prevents their expression in ESCs and so ensures maintenance of the undifferentiated state.
The researchers propose that the selective release of genes from this network leads to their expression and thus controls early development decisions that start the stem cell along the road to becoming a defined cell type. Lastly, de-regulation of Polycomb complexes has been shown to be the cause of several cancers and developmental disorders emphasising the importance of understanding Polycomb-mediated gene repression in development and disease.
Dr Sarah Elderkin, Group Leader in the Institute’s Nuclear Dynamics research programme and lead author on the Nature Genetics paper said: “Analysing the genome-wide connections of 22,225 promoters in the genome of mouse embryonic stem cells allowed us to identify a sub-set of nearly 100 promoters which form the strongest interaction network seen in the entire genome. This is exciting because the members of this sub-set encode early developmental regulators which define what the embryonic stem cell will become. This research uncovers a mechanism for how inappropriate expression of developmental genes is prevented and also suggests how genes are freed from this silencing in order for normal embryonic development to proceed.”
Funding support for this research was provided by the Wellcome Trust to Dr Sarah Elderkin, Biotechnology and Biological Sciences Research Council (BBSRC), EU and Medical Research Council (MRC) to Dr Peter Fraser and the European Commission to Dr Nicholas Luscombe as part of the FP7 EpiGeneSys Network of Excellence. The Babraham Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
PRC1 spatially restrains the mouse ESC genome. The leftmost image shows PRC1 staining as pink dots in the nucleus of an embryonic stem cell. The central diagram shows a map of interactions occurring between different chromosomes in the mouse genome. The thickness of the lines relates to strength of interaction. The rightmost figure shows interactions of all 22,000 genes throughout the genome. The cluster at the centre of this model contains key developmental genes that are silenced in embryonic stem cells by PRC1. Schoenfelder et al. Nature Genetics, 2015. The image was designed by Dr Veronique Juvin.
Like to see this research in action? Take a tour of the genome's interconnections
in our video about this research, narrated by Institute group leader Dr Sarah Elderkin.
Associated researchers (in author order):
Stefan Schoenfelder, senior postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Andrew Dimond, PhD student (Fraser lab)
Biola-Maria Javierre, postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Harry Armstrong, PhD student (Elderkin lab)
Emilia Dimitrova, PhD student (Elderkin lab)
Louise Matheson, postdoc researcher (Elderkin lab)
Mayra Furlan-Magaril, postdoc researcher (Fraser lab), Nuclear Dynamics Programme
Steven W. Wingett, researcher (Fraser lab)
Kristina Tabbada, Head of Sequencing Facility
Cameron Osborne, group leader, Babraham Institute, now at Department of Genetics & Molecular Medicine, King's College London
Peter Fraser, group leader, Nuclear Dynamics programme
Sarah Elderkin, group leader, Nuclear Dynamics programme
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used cultured mouse embryonic stem cells and breeding programmes to produce genetically-modified embryonic stem cells from early-stage mice embryos.
Please follow the link for further details of our animal research, how we use alternatives whenever possible and our animal welfare practices.
Schoenfelder et al. (2015) Polycomb repressive complex PRC1 spatially constrains the mouse embryonic stem cell genome. Nature Genetics
For more on the Promotor Capture Hi-C technique see: New technique has implications in determining the genetic basis of thousands of diseases
01 September 2015