System Biological Determination of the Epigenomic Structure-Function Relation: EpiGenSys
Lead Research Organisation:
UNIVERSITY OF OXFORD
Department Name: Sir William Dunn Sch of Pathology
Abstract
Our genetic information is stored in the base sequence encoded by our DNA, and the DNA molecules that run the length of each human chromosome are arguably the longest and most important biomolecules known. But although we now know their DNA sequences, we still know almost nothing about how that DNA is folded in 3-D space within the nucleus of a living cell. Common sense suggests there must be some underlying order within the apparent tangle. As a result, the relation of the 3-D dynamic architecture with function - the storage and expression of genetic information - remains one of the central unresolved issues of our time. It has become clear that genomes are tremendous coevolutionary and interwoven molecular storage machines able to manipulate and fabricate information: the genetic information is coded in and along these long molecules, and these molecules are continually being modified spatially and temporally through a multi-dimensional interaction and regulatory network. Therefore, a full understanding of structure-function relationships requires knowledge not only of the linear base-pair composition, but also of its structural and dynamic organization. The human genome encodes information on several levels: i) the famous DNA double helix, ii) which winds around a protein complex (the nucleosome), iii) and condenses into a higher-order 'chromatin' fiber, iv) that is folded into loops, v) which aggregate in turn into chromosomal subdomains, vi) that form 'territories', vii) which are arranged in a complex way in the nucleus. Modifications acting as a code and affecting function are found at all these levels. Therefore, in 'EpiGenSys' we have established an unique consortium of European scientists with the aim of achieving a major breakthrough in the determination and understanding of the relation between DNA sequence, the 3-D folding, and the way the system is able to access and read ('transcribe') the information. Using a truly inter-disciplinary approach, we plan to integrate the following set of projects: i) The investigation of the dynamic structure locally at the level of the nucleosome and globally at the level of the fiber. ii) The determination of intra/inter chromosomal interactions and the organization of territories. iii) The analysis of the genetic readouts - the transcriptional states - and their relation to the underlying structure. iv) The simulation (using super-computers) of the structure at the level of nucleosomes, fibers, and whole chromosomes to provide theoretical insight. v) The integration of i) to iv) into a mathematical model of the whole system that will be accessed using a special web browser that will facilitate the viewing (and manipulation) of all the different kinds of data. We expect through reiterative cycling between experiment and theory that we will be able to address a central issue of the genomic era - the way structure influences gene activity (and vice versa). Projects i) through iii) involve (wet) experimental science (cell and molecular biology), while projects iv) and v) utilize computers and mathematical modelling (and so involve mathematicians, physicists, and bioinformaticians) . PR Cook will be involved in projects ii), iii) and iv), and so will work on both sides of the cultural divide.
Technical Summary
Our genetic information is stored in the base sequence encoded by our DNA, and the DNA molecules that run the length of each human chromosome are arguably the longest and most important biomolecules known. But although we now know their DNA sequences, we still know almost nothing about how that DNA is folded in 3-D space in the nucleus of a living cell. As a result, the relation of the 3-D dynamic architecture with function - the storage and expression of genetic information - remains one of the central unresolved issues of our time. The human genome encodes information in: i) the famous DNA double helix, ii) which winds around a protein complex (the nucleosome), iii) and condenses into a higher-order 'chromatin' fiber, iv) that is folded into loops, v) which aggregate in turn into chromosomal subdomains, vi) that form 'territories', vii) which are arranged in a complex way in the nucleus. Modifications affecting function are found at all these levels. Therefore, we have established an unique consortium of European scientists ('EpiGenSys') with the aim of achieving understanding the relation between the DNA sequence, 3-D folding, and the way the system is able to access and read ('transcribe') the information. Using a truly inter-disciplinary approach, we plan to integrate the following set of projects: i) The investigation of the dynamic structure locally at the level of the nucleosome and globally at the level of the fiber. ii) The determination of intra/inter chromosomal interactions and the organization of territories. iii) The analysis of the genetic readouts - the transcriptional states - and their relation to the underlying structure. iv) The simulation (using super-computers) of the structure at the level of nucleosomes, fibers, and whole chromosomes. v) The integration of i) to iv) into a mathematical model of the whole system. PR Cook will be involved in projects ii), iii) and iv).
Planned Impact
Who will benefit from this research? We believe that 'EpiGenSys' will create a virtual lab that will help us to solve one of the central challenges of our age - the relationship between the structure and (epigenetic) function of genomes (and the human genome in particular). We will apply an unique approach integrating advanced highthroughput/high-performance technologies in cell biology, mathematics, physics and informatics to enhance our understanding of this key biological issue. 'EpiGenSys' is a true systems approach that will be applied to determine how the activities of genes in certain cells are connected to the organization (and vice versa) and how these are connected in turn to the many serious diseases (e.g., cancer, diabetes, heart disease) that are known to result from derangements in transcriptional control and epigenetic programming. Therefore we anticipate that beneficiaries will include a wide range - from scientists working in universities, through commercial enterprises who capitalize on our intellectual property, to society at large. How will they benefit from this research? 'EpiGenSys' should lead to interdisciplinary scientific publications and additional collaborations beyond those found in the consortium (estimate: ~15 publications, ~20-40 academic collaborations). Each of the technologies to be used (and their future developments), plus the synergies that might arise from their combined use, have potential for commercialization due to their uniqueness, novelty, and frontier position (e.g., concerning academic, diagnostic and commercial aspects). We anticipate that we will be able to create ~5 intellectual property rights (e.g., patent applications, market rights, licensing schemes). Notably, numerous collaborations with academic and commercial partners are already underway (~20 academic, ~10 industry). What will be done during the course of the grant to ensure that they have the opportunity to benefit from this research? Within our consortium, results will be disseminated and exploited by i) two major meetings per year where all participants meet, ii) a monthly online conference of lab heads, iii) a weekly conference of the work force, iv) regular work meetings in participants' labs, v) use of a web-based communication platform with project database and forum, vi) exchange of results via our novel Portable Genome Format (PGF) data format and the GLOBE 3D Genome platform. At the local level, we will train members of the consortium through: i) meetings, ii) online conferences, iii) work meetings/exchanges, and iv) virtual meetings using our browser/platform. At the global level that affects society at large we plan to: i) hold a workshop open to the scientist and the public, ii) 'market' our results at academic conferences, iii) generate active academic and industrial partnerships, iv) build a website with information accessible to the general public, and v) hold open media events in participating countries.
Organisations
Publications
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Brackley CA
(2013)
Nonspecific bridging-induced attraction drives clustering of DNA-binding proteins and genome organization.
in Proceedings of the National Academy of Sciences of the United States of America
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Caudron-Herger M
(2015)
Dissecting the nascent human transcriptome by analysing the RNA content of transcription factories.
in Nucleic acids research
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Diermeier S
(2014)
TNFa signalling primes chromatin for NF-?B binding and induces rapid and widespread nucleosome repositioning.
in Genome biology
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Kelly S
(2015)
Exon Skipping Is Correlated with Exon Circularization.
in Journal of molecular biology
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Kelly S
(2015)
Splicing of many human genes involves sites embedded within introns.
in Nucleic acids research
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Kolovos P
(2012)
Enhancers and silencers: an integrated and simple model for their function.
in Epigenetics & chromatin
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Larkin JD
(2013)
Promoter type influences transcriptional topography by targeting genes to distinct nucleoplasmic sites.
in Journal of cell science
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Larkin JD
(2012)
Dynamic reconfiguration of long human genes during one transcription cycle.
in Molecular and cellular biology
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Melnik S
(2011)
The proteomes of transcription factories containing RNA polymerases I, II or III.
in Nature methods
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Papantonis A
(2012)
TNFa signals through specialized factories where responsive coding and miRNA genes are transcribed.
in The EMBO journal
Description | This project was part of a European consortium. The focus of the group in Oxford (Cook/Papantonis) was on the changes occurring when human cells were treated with a powerful cytokine - TNFa - which plays a role in mounting the defense against infection. A huge amount of data has been amassed using high-throughput sequencing to assess which genes became more (or less) active. In addition, the response of one gene was studied in great detail. Results showed that the molecular machines that copy DNA into RNA do not track like locomotives down the template (as all the textbooks would have us believe); rather, they become transiently immobilized in discrete sites which we call 'factories' when they are active. Furthermore, some of these factories specialize in transcribing different groups of genes. Consequently, this research is changing the way these vital machines work, and how the human genome is organized in three-dimensional space. |
Exploitation Route | If our ideas are correct, they will change the way we think RNA polymerases work, how genes become active, and the way the genome is organized. |
Sectors | Healthcare |
URL | http://users.path.ox.ac.uk/~pcook/ |
Description | This project involved fundamental biomedical research. Therefore it contributed to the quality of like health and creative output of the nation. |
First Year Of Impact | 2011 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Cultural |