Research from the Babraham Institute has revealed for the first time that genes work together by huddling in clusters inside the nucleus -- the information centre of a cell. These findings, published in the online edition of the journal Nature Genetics, represent a paradigm shift in our understanding of how the genome is spatially organised in relation to gene expression. It marks the first step towards a 'virtual nucleus', a dynamic tool simulating interactions in the nucleus, which could revolutionise computer-based drug design.
The team reveal that spatial networks of active genes with related physiological roles congregate in 'hot spots' in the nucleus known as transcription factories. The research also offers insight into the causes of cancer since chromosome breakages, characteristic of many cancers, are thought to occur in transcription factories. This new discovery about how genes work in 3D will help us understand healthy development as well as disease and how cells acquire specialised functions.
Dr Peter Fraser, Head of Babraham's Laboratory of Chromatin and Gene Expression explained, "The specific three-dimensional arrangements of the genome in different cell types represent a missing link in our understanding of how our genome works. To understand how cells can change from one type to another, a critical question for stem cell therapies, we need to understand what causes the genes to come together in this way."
Developing 'a virtual nucleus', an interactive computer model of the part of the cell where genes are actively working, may shed light on these processes. Dr Fraser added, "Identifying the genes that co-associate in shared transcription factories and developing a 'virtual nucleus' potentially opens the door for more effective drug design. These are the first steps in a very long journey that will lead to computer models simulating genome behaviour and function in development, differentiation, health and disease."
Highly coordinated chromosomal choreography leads genes and the sequences controlling them, which are often positioned huge distances apart on chromosomes, to these 'hot spots'. Once close together within the same transcription factory, genes get switched on (a process called transcription) at an appropriate level at the right time in a specific cell type. This is the first demonstration that genes encoding proteins with related physiological role visit the same factory.
The team use sophisticated imaging techniques to see into the nucleus in three-dimensions. Fluorescent tags pinpoint the hot-spots of activity in the nucleus, revealing that DNA, rather than transcriptional machinery, is the most mobile element and that multiple genes share transcription factories.
Having a common goal, such as producing all the components needed to make haemoglobin, could be a factor behind genes gravitating to a particular factory. Dr Stefan Schoenfelder, one of the lead authors explained, "While the transcriptional machinery has been studied in great detail, less is known about the organisation of this machinery in 3D space within the nucleus. Examining the genes expressed by erythroid cells (precursors of red blood cells), showed that during transcription genes do not share factories with just any other gene. Particular groups of genes prefer to share factories and have preferred transcription partners. And genes whose transcription is regulated by the same transcription factors (protein molecules that attach to genes and switch on transcription) are frequently found clustered at the same transcription factory."
This is the first time that genome-wide screening has been conducted, identifying extensive 3D spatial networks of active genes involved in related physiological processes. This work at Babraham, an institute of the Biotechnology and Biological Sciences Research Council (BBSRC), indicates that where and how genes are organised spatially within the nucleus, and how they get there, are important factors determining gene expression in specific tissues and developmental processes. The research was funded by BBSRC and MRC.
The findings also help to explain how certain cancers occur. Numerous studies have shown that the organisation of the nucleus is one of the most obvious changes when cells become cancerous; cancers are frequently associated with a process called chromosomal translocation -- this is where breaks in chromosomes then reattach incorrectly leading to a fusion between different genes. How this happened, considering the extensive distances between the genes involved, remained elusive until the transcription factory model was proposed.
The impact that genome organisation has on susceptibilities to cancers like leukaemia, is being investigated by Dr Cameron Osborne, a Babraham Group Leader. Genes frequently found fused together in Burkitt lymphoma, a common blood cancer, have been shown to commute to the same transcription factory to be activated. It is while multiple genes are docked simultaneously at a factory that chromosomal translocations are believed to occur. Dr Osborne explained, "A key aim is to see whether genes involved in translocations associated with specific cancers are preferentially found together at transcription factories. If so, this could represent a common and fundamental step in cancer development. Ultimately, these studies will have wide-ranging implications in human health and disease and may point the way to novel forms of treatment for cancer patients."
- schoenfelder S, Sexton T, Chakalova L, Cope Nf, Horton A, Andrews S, Kurukuti S, Mitchell Ja, Umlauf D, Dimitrova Ds, Eskiw Ch, Luo Y, Wei Cl, Ruan Y, Bieker Jj, and Fraser P. Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells. Nature Genetics, 2009 DOI: 10.1038/ng.496
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