Babraham scientists' 3D view of genes-at-work is paradigm shift in genetics

Cambridge 14 December 2009Research 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 on-line 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 revealed 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.

Cells in the mammalian body are able to perform numerous functions, yet the genetic information they contain is, with very few exceptions, identical. This is accomplished by expressing different sets of genes in different cell types. Gene expression starts with a process called transcription, where the genetic information is transcribed into RNA. In mammals transcription takes place in dedicated nuclear compartments called transcription factories. Recent studies showed that genes "commute" to these factories to be activated and can undergo dynamic long-range interactions with other genes located on either the same chromosome or on other chromosomes whilst in a transcription factory.

The total number of expressed genes in a cell is far greater than the number of factories and multiple genes have been shown to share transcription factories. The RNAs act as messengers, carrying the instructions to produce specific proteins, the work horses of the cell. The identity of a cell and the tasks it performs ultimately depend on the regulation of transcription - this determines the subset of genes to express and at what level.

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 co-ordinated 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 used 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."

The paper titled "Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells" is written by Schoenfelder S., Sexton T., Chakalova L., Cope N.F., Horton A., Andrews S., Kurukuti S., Mitchell J.A., Umlauf D., Dimitrova D.S., Eskiw C.H., Luo Y., Wei C-L, Ruan Y., Bieker J.J., Fraser P. It appeared in Nature Genetics.

The Babraham Institute is a charitable organisation devoted to biomedical research and is an institute of the Biotechnology and Biological Sciences Research Council (BBSRC). The Institute's research is focused on understanding the biological events that underlie the normal functions of cells and on how their failure or abnormality may lead to disease. As such, Institute scientists are striving to find cures for conditions where there is currently no treatment or where the existing treatment is not fully effective or causes serious side effects.

The latest technologies are being used to study the basis of conditions such as neuro-degenerative disorders, birth defects, cancer and diseases of the immune and cardiovascular systems. With a strategic focus on "healthy ageing", novel approaches for tackling chronic diseases and public health concerns like obesity are being discovered. The Institute's innovative research is commercialised through Babraham Bioscience Technologies (BBT) Ltd., which also manages Babraham's vibrant Bioincubator on the Babraham Research Campus, six miles south-east of Cambridge.

The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around GBP 450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health care and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.

The Babraham Institute, Institute for Animal Health, Institute of Food Research, John Innes Centre and Rothamsted Research are Institutes of BBSRC. The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.

Source: The Babraham Institute

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