3D organization of the mammalian genome

Lead Research Organisation: Babraham Institute
Department Name: Nuclear Dynamics

Abstract

The human genome project has given us the entire DNA sequence of building blocks of the human genome, but we still know little about how the genome is controlled to express the correct subsets of genes in the different cell types of the body. This proposal will assess for the first time the 3 dimensional arrangement of the entire genome in a particular cell type. Recent scientific evidence suggests that the genome is highly organized within the space of the cell nucleus in such a way as to maximize efficient expression of the desired or required subset of genes while keeping all of the other genes silent. This radically changes the way that scientist think about the genome and gene regulation in general. Genes are not functioning in isolation but preferentially grouping together with other similarly regulated genes to cooperate in their control and efficient expression. The results will have fundamental implications for modern genomic medicines such as gene therapy and stem cell therapies as well as give important clues to health and genetic diseases such as cancer. This knowledge is vitally important to ensure that future genomic and cell therapies are safe, reliable and designed from a position of knowledge and insight rather than trial and error.

Technical Summary

Surprisingly little information is available to describe how the genome is organized within the three-dimensional space of the nucleus. It has been known for some time that individual chromosomes take up preferred positions relative to one another in the nucleus and that these arrangements are tissue-specific, suggesting a role in gene expression. Recent technological advances are beginning to uncover spatial relationships and interactions between genes and regulatory elements in the nucleus and are revealing an unexpectedly extensive network of communication within and between chromosomes. A crucial question is the extent to which this organization affects gene function. Our preliminary studies shows that similarly regulated genes in cis and trans preferentially cluster at a limited number of transcription sites in the nucleus, suggesting that individual transcription factories are specialized to transcribe specific networks of genes. These data indicate that specific ?active? genes are more likely to be transcribed if they associate with specialized factories containing other genes that utilize the same trans-acting factors for expression, suggesting that genes cooperate for efficient transcription. In this proposal we will use a novel unbiased technology to assess genome-wide, interactions between all transcriptionally active genes at transcription factories. The data will permit the elucidation of all transcription networks and produce the first, functional, 3D maps of the genome, providing unprecedented insights into the relationships between genome conformation and function. We will test the molecular mechanisms that may be responsible for genome organization using genetically modified mice in which mutant forms of a transcription factor have been knocked in to the endogenous locus. These experiments are essential to understand fundamental mechanisms of genome function and regulation in health and diseases such as cancer. In addition, this knowledge will form part of an essential foundation that must underpin modern genomic medicines such as gene therapy and stem cell therapies.

Publications

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Cope NF (2010) The yin and yang of chromatin spatial organization. in Genome biology

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Cope NF (2009) Chromosome conformation capture. in Cold Spring Harbor protocols

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Edelman LB (2012) Transcription factories: genetic programming in three dimensions. in Current opinion in genetics & development

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Eskiw C (2009) Inverted rod nuclei see the light. in Nature cell biology

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Eskiw CH (2010) Transcription factories and nuclear organization of the genome. in Cold Spring Harbor symposia on quantitative biology

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Kang J (2011) A dynamical model reveals gene co-localizations in nucleus. in PLoS computational biology

 
Description EU large integrated project
Amount £800,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2011 
End 12/2016
 
Title Pathway of gene recruitment to transcription factories 
Description Identified factors in the Pathway of gene recruitment to transcription factories 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Improved understanding of chromatin dynamics in transcriptional control 
 
Title e4C array data 
Description Genome wide data on transcriptional interactomes of the globin genes 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2010 
Provided To Others? Yes  
Impact changed perspective on transcriptional organization. 
 
Title enhanced 4C (e4C) 
Description Assay to detect genomic sequences in proximity in the nucleus. 
Type Of Material Technology assay or reagent 
Year Produced 2009 
Provided To Others? Yes  
Impact Changed perspectives in transcriptional organization 
 
Description Participation in Network of Excellence 
Organisation European Commission
Country European Union (EU) 
Sector Public 
PI Contribution Associate membership in EU Network of Excellence
Impact none yet
Start Year 2011
 
Description Role of Klf1 in transcriptional induction and nuclear organization 
Organisation Agency for Science, Technology and Research (A*STAR)
Department Genome Institute of Singapore
Country Singapore 
Sector Academic/University 
PI Contribution Did all the experiments, except the DNA sequencing
Collaborator Contribution contributed knock-out cell lines with inducible factors contributed knockin mouse linesPerformed high-throughput sequencingsupplied antibodies
Impact Publications
Start Year 2008
 
Description Role of Klf1 in transcriptional induction and nuclear organization 
Organisation Icahn School of Medicine at Mount Sinai
Department Developmental and Regenerative Biology
Country United States 
Sector Academic/University 
PI Contribution Did all the experiments, except the DNA sequencing
Collaborator Contribution contributed knock-out cell lines with inducible factors contributed knockin mouse linesPerformed high-throughput sequencingsupplied antibodies
Impact Publications
Start Year 2008
 
Description Role of Klf1 in transcriptional induction and nuclear organization 
Organisation University of Chicago
Department Section of Hematology/Oncology
Country United States 
Sector Academic/University 
PI Contribution Did all the experiments, except the DNA sequencing
Collaborator Contribution contributed knock-out cell lines with inducible factors contributed knockin mouse linesPerformed high-throughput sequencingsupplied antibodies
Impact Publications
Start Year 2008
 
Description Researcher in residence 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact 30 advanced students attended workshop

reported higher than expected interest from pupils
Year(s) Of Engagement Activity 2011
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Approx 90 students on three oocasions attended talks on stem cells and epigenetics

reported higher than expected interest from pupils
Year(s) Of Engagement Activity 2008,2009
 
Description Schools day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Approx 10 students visited lab for the day to do hands on experiments.

reported higher than expected interest from pupils
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011