Three-dimensional interrogation of gene regulation using next generation chromatin conformation capture and super-resolution imaging.

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To form the cells and tissues that make up our bodies requires exquisite control of the activity of our genes. The protein products of genes form the functional and structural components of our cells. Gene expression is controlled by a subgroup of proteins called transcription factors which bind specific sequences in our DNA (also called the "genome"). If this control is altered by sequence changes in the genome then the correct function of our cells is affected and can lead to disease: the particular disease or diseases depend on the types of cells affected. Scientists have become very good at finding the ~ 2% of our DNA that encodes for protein, however it has become clear that other parts of our genome (called regulatory elements) play a critical role in controlling our genes.Regulatory elements are scattered throughout the genome and novel methods that identify such elements show that it is very difficult to understand which gene they control as they do not necessarily control nearby genes, but may affect quite distant genes. A technique called chromosome conformation capture can link regulatory elements to the genes they control by mapping their physical interactions, which are necessary for their activity, but this still does not explain why certain elements can contact and regulate some specific genes but not others. This is an important question because changes in the genome sequence can prevent regulatory elements talking to the correct genes or cause them to talk to the wrong genes with very damaging consequences. The mechanism that makes these interactions specific is unknown, but is thought to be due to the three dimensional arrangement of the genome in the nucleus. The work in this proposal adapts technologies developed by a collaboration between molecular biologists, chemists and computational scientists to visualize these interactions in 3D to understand how certain regulatory elements work with specific genes and how changes in the genome can alter this and cause disease.