The role of spatial nuclear organisation in genome function

The linear sequence map of the DNA that makes up our 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 cell 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. A particularly important question is how genes are controlled in time and space by elements in our genome called enhancers that can located far away from the genes that they control. This is an important area of human genetics because most of the common genetic variation between individuals in a population that affects our life-time risk of developing disease, lies in enhancers. 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.

The regulation of gene expression is controlled by enhancers that are often located at very large genomic distance from their target genes. Mutation of enhancers underlies many cases of severe human developmental disorders and common sequence variation at enhancers contributes to a large proportion of complex genetic disease and quantitative traits. Functional interpretation of the DNA sequence variation revealed by large-scale whole human genome sequencing efforts requires a much better understanding of how enhancers work and is a major challenge in human genomics.
We will probe mechanisms of chromosome folding linked to enhancer function and to spatial positioning in the nucleus. To gain mechanistic insight into the molecular events required to activate a gene from a distance, we will use multi-disciplinary approaches – from high-throughput chromatin profiling to advanced optical imaging - integrated with synthetic biology tools that allow us to dissect cause/consequence relationships between chromatin organisation and genome function. We will test models of enhancer-promoter communication and will determine what factors are required to bind at enhancers in order to instigate the different steps of transcription. We will focus on exemplar loci that are paradigms for long-range cis-regulation (e.g. Shh and Pax6) but, with collaborators, will also help drive the functional follow-up of loci identified by genome-wide association studies (GWAS) and that involve common genetic variation at enhancers.