ScienceDaily (Dec. 16, 2009) — 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.
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Journal Reference:
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
Article abstract
Nature Genetics
Published online: 13 December 2009 | doi:10.1038/ng.496
Preferential associations between co-regulated genes reveal a transcriptional interactome in erythroid cells
Stefan Schoenfelder1,6, Tom Sexton1,5,6, Lyubomira Chakalova1,5,6, Nathan F Cope1, Alice Horton1, Simon Andrews2, Sreenivasulu Kurukuti1,5, Jennifer A Mitchell1,5, David Umlauf1,5, Daniela S Dimitrova1, Christopher H Eskiw1, Yanquan Luo3, Chia-Lin Wei3, Yijun Ruan3, James J Bieker4 & Peter Fraser1
Abstract
The discovery of interchromosomal interactions in higher eukaryotes points to a functional interplay between genome architecture and gene expression, challenging the view of transcription as a one-dimensional process. However, the extent of interchromosomal interactions and the underlying mechanisms are unknown. Here we present the first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues. Our results show that the active globin genes associate with hundreds of other transcribed genes, revealing extensive and preferential intra- and interchromosomal transcription interactomes. We show that the transcription factor Klf1 mediates preferential co-associations of Klf1-regulated genes at a limited number of specialized transcription factories. Our results establish a new gene expression paradigm, implying that active co-regulated genes and their regulatory factors cooperate to create specialized nuclear hot spots optimized for efficient and coordinated transcriptional control.
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Laboratory of Chromatin and Gene Expression, Babraham Research Campus, Cambridge, UK.
Bioinformatics Group, The Babraham Institute, Babraham Research Campus, Cambridge, UK.
Genome Institute of Singapore, Singapore, Singapore.
Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York, USA.
Current addresses: Institute of Human Genetics, Montpellier Cedex 5, France (T.S.); Research Centre for Genetic Engineering and Biotechnology, Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia (L.C.); Division of Cancer Sciences and Molecular Pathology, Section of Pathology and Gene Regulation, University of Glasgow, Glasgow, UK (S.K.); Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada (J.A.M.); Institute of Genetics and Molecular Cell Biology, Illkirch Cedex, France (D.U.).
These authors contributed equally to this work.
Correspondence to: Peter Fraser1 e-mail: peter.fraser@bbsrc.ac.uk
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COMENTÁRIOS IMPERTINENTES DESTE BLOGGER:
Eu já posso ler as manchetes em revistas de divulgação científica popular: "é mais complexo do que os cientistas esperavam".
Do artigo:
“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.”
Minha pergunta causticante:
Onde é que fica o papel de processos aleatórios, acaso, necessidade em tudo isso? NIHIL, NADA, ZERO!!!
"DNA, rather than transcriptional machinery, is the most mobile element"
FROM THE FOLLOWING ARTICLE: Replication and transcription: Shaping the landscape of the genome, by Lyubomira Chakalova, Emmanuel Debrand, Jennifer A. Mitchell, Cameron S. Osborne & Peter Fraser, Nature Reviews Genetics 6, 669-677 (September 2005)
http://www.nature.com/nrg/journal/v6/n9/fig_tab/nrg1673_F5.html
É por isso que eles dirão: "É muito mais complexo do que nós imaginávamos!"
Vai ficar cada vez mais complexo ainda, cumpadi!!! É design inteligente, sô!!!
