Spatial Organisation of the Human Genome

 

Summary

Despite its immense length, the linear sequence map of the human genome is an incomplete description of our genetic information. This is because information on genome function and gene regulation is also encoded in the way that the DNA sequence is folded up with proteins within chromosomes and within the nucleus. Our work to understand the three-dimensional folding of the genome, and how this controls how our genome functions.

 

 

 

Approach, Progress and Future Work

We take a multidisciplinary approach, using cytological, genetic and biochemical methods to understand genome spatial organisation. However, a main feature of our work is the use of visual assays to investigate how the genome is folded up. To do this we combine fluorescence in situ hybridisation (FISH) and digital microscopy with the use of automated image analysis software.

 

Key Publications

1. Finlan, L.E.; Sproul, D.; Thomson, I.; Boyle, S.; Kerr, E.; Perry, P.; Ylstra, B.; Chubb, J.R., and Bickmore, W.A. Recruitment to the nuclear periphery can alter expression of genes in human cells. PLoS Genet 4(3): e1000039, 2008
   PubMed Abstract
2. Morey, C.; Da Silva, N.R.; Kmita, M.; Duboule, D. and Bickmore, W.A. Ectopic nuclear reorganisation driven by a Hoxb1 transgene transposed into Hoxd. J Cell Sci 121(Pt 5):571-577, 2008
   PubMed Abstract
3. Matarazzo, M.R., Boyle,S., D´Esposito, M. and Bickmore, W.A. . Chromosome territory re-organisation in a human disease with altered DNA methylation. Proc Natl Acad Sci 104:16546-16551, 2007
   PubMed Abstract
4. Morey C, Da Silva NR, Perry P and Bickmore WA Nuclear re-organisation and chromatin decondensation are conserved, but distinct, mechanisms linked to Hox gene activation. Develop 134:909-919, 2007
   PubMed Abstract
5. Sutherland, H,G,; Newton, K.; Brownstein, D.G.; Holmes, M.C.; Kress, C.; Semple, C.A. and Bickmore, W.A. Disruption of Ledgf/Psip1 results in perinatal mortality and homeotic skeletal transformations.
   Mol Cell Biol 26:7201-7210, 2006
   PubMed Abstract
6. Chambeyron, S.; Bickmore, W.A. Chromatin decondensation and nuclear reorganization of the HoxB locus upon induction of transcription. Genes Dev 18:1119-1130, 2004
   PubMed Abstract
   
7. Gilbert, N.; Boyle, S.; Fiegler, H.; Woodfine, K.; Carter, N.P. and Bickmore, W.A. Chromatin architecture of the human genome; gene-rich domains are enriched in open chromatin fibers. Cell 118:555-566, 2004
   PubMed Abstract

Collaborations and Funding

Our work is funded by: Medical Research Council, James S.McDonnell Foundation, and the European Union FP6 and Wellcome Trust.

 

Lab Members

Current lab members involved in this work are:

• Shelagh Boyle
• Elizabeth Kerr
• Pradeepa Madapura-Marulasiddappa
• Pierre Therizols
• Robert Illingworth
• Leisha Nolen

Wendy Bickmore's Home Page

 

 

 

 

These fall into three parts:

1. Spatial organisation of the genome
2. Nuclear re-organisation during development
3. Mutating genes encoding chromosomal and nuclear proteins

 

1. Spatial organisation of the genome

In the nucleus, individual chromosomes occupy discrete territories. We are examining the spatial organisation of human and mouse chromosomes and genes in the nucleus (Fig.1) and how this organisation is changed, for example, during development and in certain genetic diseases.

 

Figure 1. Human nucleus (blue) hybridised to reveal the territories of two human chromosome pairs (red and green).

 

 

 

2. Nuclear re-organisation during development

We have revealed dramatic re-organisation of an important gene cluster (the Hox genes) in the nucleus during embryonic development showing how the control of this complex level of genome organisation may contribute to directing gene expression in time and space during development.

3. Mutating genes encoding chromosomal and nuclear proteins

There is a growing awareness that the nucleus is compartmentalised, so that proteins with related functions often co-localise in space. We used a gene-trap screen to identify genes that encode proteins localising to specific nuclear compartments (Fig. 2). This is a powerful way to address our ignorance of the molecular composition of the mammalian nucleus and to assign biological function to genes by ascertaining the sub-cellular destination of their products. Recently, we identified a novel chromosomal protein - LEDGF this way. This protein has recently been shown to be important in the biology of the HIV virus.

 

We have also developed a searchable Nuclear Protein Database that contains information on protein structure, function and sub-cellular localisation for >2100 mammalian proteins.

 

Figure 2. Nuclei (blue) from two gene trap lines. On the left the protein (green) encoded by the trapped gene is located at the periphery of the nucleus. In the nucleus on the right the protein is located in speckled domains within the nucleus.

 

Purpose

Our work is aimed at understanding the genome at a level beyond that of the DNA sequence alone. We are investigating how the genome is organised within the nuclear space, both within normal, and diseased, cells and also how this organisation changes during development. We want to know how this level of organisation influences gene and chromosome function.