Integrating genome structure and function

Lead Research Organisation: MRC Human Genetics Unit

Abstract

Each human cell contains 2m of DNA, yet our genome has to function within the context of the cell nucleus that is only 10 thousandths of a mm in diameter. This remarkable feat of packing is achieved by folding the DNA sequence up with proteins, to form a structure called chromatin. We now realise that chromatin not only allows the DNA to fit inside of the cell, but that it also controls the way that the DNA is read. Using a combination of biochemistry and microscopy, we are investigating what different chromatin structures there are in mammals, and how they are normally regulated and changed during development to allow different sets of genes to be switched on and off. Once we understand the chromatin architecture of the normal genome, this will allow us to understand how altered chromatin structure can contribute to disease.

Technical Summary

We want to understand how chromatin is organized in the human cell nucleus, how this influences gene expression, and how it is altered during normal development and in disease. A range of technical approaches (biochemical, biophysical and cytological) now allows us to analyse multiple levels of chromatin structure, from the nucleosome through to nuclear organisation. Combined with the use of genomic microarrays, this means that we can determine chromatin structures, not only at individual genes, but also across large regions of the genome. An example of the latter are Hox loci, which encode genes important for patterning of the developing embryo. To study how chromatin structures are changed during early embryonic development, we use the mouse as a model system, taking advantage of pre-existing models for Hox gene regulation.||We have recently begun to uncover alterations in normal spatial genome organization in human diseases.||As well as observing the way that the genome is normally organized, we have developed a method to experimentally alter the spatial organization of the human genome within the nucleus in tissue culture cells. We have used this system to show that recruiting genes to the nuclear periphery is sufficient to mediate their transcriptional repression. We suggest that spatial organization is used to regulate gene expression during mammalian development.||Lastly, we complement our study of the organisation of DNA by analysing the function of specific nuclear proteins that are involved in chromatin structure and gene regulation, and that we have identified by gene-trapping in mouse embryonic stem cells.

Publications

10 25 50
 
Description Scientific Advisory Board Sanger Institute
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
 
Description BBSRC project grant (Integrating developmental pathways and chromatin structure during lineage specifcation)
Amount £247,601 (GBP)
Funding ID BB/H008500/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 02/2010 
 
Description Breakthrough Breast Cancer Centre
Amount £195,000 (GBP)
Organisation Breakthrough Breast Cancer 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2008 
 
Description ERC advanced grant
Amount £1,487,000 (GBP)
Funding ID 249956 
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 01/2010 
 
Description EuFP6 Epigenome NoE
Amount £118,000 (GBP)
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 01/2006 
 
Description Wellcome Trust Project grant (Investigating functions of the chromosomal protein Ledgf)
Amount £181,700 (GBP)
Funding ID 085767 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2008 
End 12/2011
 
Title Gene traps 
Description Gene-trap knockout mouse models for novel nuclear proteins 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2006 
Provided To Others? Yes  
Impact These animal models have been used in several publications by other research groups, and the cell lines developed from these animals have been distributed to groups working onHIV infections. 
 
Title NPD 
Description A searchable & expertly curated database on the structure, localisation and functions of proteins in the mammalian nucleus. It also contains teaching tools about nuclear compartments/structures 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact This database continues to be widely accessed and cited by the community and highlighted at international meetings. It has been used, in collaboration with Department of Informatics (Edinburgh University), to develop assisted curation tools using Natural Language/Information retrieval algorithms. 
URL http://npd.hgu.mrc.ac.uk/user/
 
Title lacO 
Description Human cell lines each containing arrays of the lacO repeat inserted into specific chromosomes. 
Type Of Material Cell line 
Year Produced 2007 
Provided To Others? Yes  
Impact These cell lines are now being used to experimentally manipulate the organisation of the human nucleus. 
 
Title NPD 
Description Expertly curated database for mammalian nuclear proteins 
Type Of Material Database/Collection of data 
Year Produced 2010 
Provided To Others? Yes  
Impact Not known 
URL http://npd.hgu.mrc.ac.uk/user/about
 
Description Nuclear Organisation in Cancer 
Organisation NEC Corporation
Country Japan 
Sector Private 
PI Contribution NEC funded a technician in my lab for 2 years to investigate whether our technical expertise could be applied to a better molecular understanding of how nuclear organisation is perturbed in clinical biopsies from breast cancer. A paper has been recently accepted on this work and, although the funding for this collaboration has now finished, we are still actively collaborating. As a result of the work initiated on this collaboration we have been awarded a 5 year grant form the charity Breakthrough Breast Cancer and have initiated close contacts with the local Consultant pathologist and breast cancer surgeon at NHS Lothian
Collaborator Contribution NEC funded a technician in my lab for 2 years to investigate whether our technical expertise could be applied to a better molecular understanding of how nuclear organisation is perturbed in clinical biopsies from breast cancer. A paper has been recently accepted on this work and, although the funding for this collaboration has now finished, we are still actively collaborating. As a result of the work initiated on this collaboration we have been awarded a 5 year grant form the charity Breakthrough Breast Cancer and have initiated close contacts with the local Consultant pathologist and breast cancer surgeon at NHS Lothian
Impact NEC funded a technician in my lab for 2 years to investigate whether our technical expertise could be applied to a better molecular understanding of how nuclear organisation is perturbed in clinical biopsies from breast cancer. A paper has been recently accepted on this work and, although the funding for this collaboration has now finished, we are still actively collaborating. As a result of the work initiated on this collaboration we have been awarded a 5 year grant form the charity Breakthrough Breast Cancer and have initiated close contacts with the local Consultant pathologist and breast cancer surgeon at NHS Lothian Changes in chromatin structure during processing of wax-embedded tissue sections. Kerr E, Kiyuna T, Boyle S, Saito A, Thomas JS, Bickmore WA. Chromosome Res. 2010 Sep;18(6):677-88. Epub 2010 Jul 27.PMID: 20661639
 
Description Nuclear consequences of translocation chromosomes in humans 
Organisation University of Lausanne
Department Center for Integrative Genomics
Country Switzerland 
Sector Academic/University 
PI Contribution Training in the use of fluorescence in situ hybridisation to analyse human chromosomes in the nucleus. Algorithms for the quantification of nuclear organisation.
Collaborator Contribution Exchange of biological resources. Joint publication
Impact The effect of translocation-induced nuclear reorganization on gene expression. Harewood L, Schütz F, Boyle S, Perry P, Delorenzi M, Bickmore WA, Reymond A. Genome Res. 2010 May;20(5):554-64. Epub 2010 Mar 8.PMID: 20212020
Start Year 2007
 
Description Nuclear organisation in breast cancer 
Organisation Western General Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Developed methodology for the analysis of nuclear organisation in human archival tissue specimens
Collaborator Contribution Expert pathology advice. Access to archival human tissue
Impact Changes in chromatin structure during processing of wax-embedded tissue sections. Kerr E, Kiyuna T, Boyle S, Saito A, Thomas JS, Bickmore WA. Chromosome Res. 2010 Sep;18(6):677-88. Epub 2010 Jul 27.PMID: 20661639
Start Year 2007
 
Description Nuclear reorganisation in response to estrogen 
Organisation University of Toulouse
Department Department of Molecular Biology
Country France 
Sector Academic/University 
PI Contribution Exchange of data. Joint paper-writing
Collaborator Contribution Exchange of data, and a joint publication Pubmed ID 20421946
Impact Activation of estrogen-responsive genes does not require their nuclear co-localization. Kocanova S, Kerr EA, Rafique S, Boyle S, Katz E, Caze-Subra S, Bickmore WA, Bystricky K. PLoS Genet. 2010 Apr 22;6(4):e1000922.PMID: 20421946
Start Year 2007
 
Description human disease with altered DNA methylation 
Organisation National Research Council
Department Institute of Genetics and Biophysics (IGB)
Country Italy 
Sector Public 
PI Contribution Provided specialist training, expertise and data acquisition and analysis
Collaborator Contribution provided biological samples
Impact PMID: 17923676
Start Year 2006
 
Title Genome Wide Analysis of Chromatin Architecture 
Description A novel method for genome-wide analysis of chromatic architecture 
IP Reference WO2006024851 
Protection Patent granted
Year Protection Granted 2006
Licensed No
Impact A novel method for genome-wide analysis of chromatic architecture which may be useful as a prognostic tool and/or diagnostic in fields such as cancer. Patent filed
 
Description Diabetes UK 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Visit from Diabetes UK
Year(s) Of Engagement Activity 2016
 
Description Fabrics of Life workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Workshop on Epigenetics with Textile Design students at Central St Martins College of Art & design, London

Workshop was filmed and clips posted on YouTube by the students
Year(s) Of Engagement Activity 2007
 
Description MRC Festival of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Participated at MC Festival of Science event held in a local shopping centre
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/news-2017/people-powered-dna-research
 
Description MRC Human Genetics Unit eye patient engagement 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact As part of the Eye Development & Degeneration conference, the HGU hosted a patient-facing event, welcoming 40 patients suffering from vision-impairing conditions:
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/news-2017/eye-engagement-2017
 
Description MSP visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Visit to MRC Human Genetics Unit by two MSPs
Year(s) Of Engagement Activity 2016
 
Description RSB Biology teachers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Talk to ~100 Biology teachers at event organised by Royal Society of Biology
Year(s) Of Engagement Activity 2017
 
Description RSE@schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Mutiple talks to Higher Biology students at various schools around Scotland

Talk was video recorded for transmission to other students in the schools
Year(s) Of Engagement Activity 2008,2009
 
Description School visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact ~ 35 students and teachers attended a lunch time talk as part of their science and engineering club

School asked that this be a regular annual activity
Year(s) Of Engagement Activity 2010,2011,2012
 
Description Science parliament 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact 20 pupils spent a whole day disussing the ethics and issues around stem cell research. They held a formal debate at the end of the day.

Event likely to be repeated at multiple locations next year
Year(s) Of Engagement Activity 2010
 
Description Short film premier and Q&A session on Diabetes 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact On the eve of World Diabetes Day (14th November 2017), a new short film was launched - "Diabetes and Stem Cells". This 15-minute film was the result of a collaboration between EuroStemCell and HumEn, two EU-funded research partnerships.

The documentary tells the story of how scientists are exploring the possibility of using lab grown cells as a therapy for those affected by diabetes. It includes hand-drawn animations by award-winning animator Cameron Duguid and footage of young people from Diabetes UK visiting the IGMM.

This public event attracted a diverse, mixed audience and the positive ambience encouraged a very open and invigorating discussion after the film premiere.
Year(s) Of Engagement Activity 2017
URL https://www.ed.ac.uk/mrc-human-genetics-unit/news-and-events/news-2017/diabetes-stem-cells-short-fil...
 
Description Women in Science, Dundee 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Talk on career for Women in Science day, in Dundee
Year(s) Of Engagement Activity 2016