Wendy Bickmore: Spatial Organisation of the Human Genome
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 tries to understand the three-dimensional folding of the genome, and how this controls how our genome functions in normal development and how this may be perturbed in disease.
- Chromatin Folding
- Nuclear Organisation
We examine the spatial organisation of human and mouse chromosomes and genes in the nucleus and how this organisation is changed, for example, during development and in certain genetic diseases. We use microscopy to follow the folding path of specific gene loci as they are activated or switched off, and to identify the proteins that bring about this folding (Fig. 1). A particular interest is whether regulatory elements (enhancers) control their target genes – which may be located a million base pairs away -by chromatin looping (Fig 2) .
Chromatin is not randomly organised in the nucleus. Gene-poor and some silenced loci are found preferentially at the periphery of the nucleus. Structural rearrangements of the human genome e.g. translocations can disrupt this organisation. Within individual chromosomes, the gene-rich parts can be seen looping out of the rest of the chromosome territory and away from the nuclear periphery (Fig 3). Some epigenetic mechanisms for controlling gene expression act by compacting genes in the nucleus.
We have also developed a searchable Nuclear protein database that contains information on protein structure, function and sub-cellular localisation for >2500 mammalian proteins.
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.
Approach, Progress and Future Work
We take a multidisciplinary approach, using cytological, genetic, biochemical and synthetic biology methods to understand genome spatial organisation. However, a prominent 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.