The regulation of transcriptional bursting by superenhancers

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The human body is made up of trillions of cells. Each single cell contains the information in its DNA to encode a new individual. The code comes in the form of genes that contain the information to make specific proteins, and regulatory elements (called enhancers) that switch the genes on and off in different tissues, and at different times in development. It is hard to imagine that one could line up 5 or 6 cells across a human hair (60-70 microns). Development of the first microscopes in the 17th century enabled scientists to see such minute structures for the first time. Over the next 300 years, microscopes have been developed so that we can now visualise subdomains that stretch across just one thousandth of the diameter of the cell (60-70 nanometers). So called "super-resolution" microscopes are now enabling us to visualise how enhancers and genes interact to read the genetic code and over the past decade it has been possible to visualise the code being read by creating real-time movies. This new approach to understanding biology at such high resolution, referred to as the nanoscale, is at the limits of what is currently possible in studying biology and so it has been critical to establish very well understood systems that enable us to verify these nanoscale findings by comparing new results with previous analyses of the model locus. In our laboratory we study expression of a gene encoding alpha-globin which contributes to the synthesis of the red cell pigment (haemoglobin). How this gene is switched on and off is probably better understood that almost any other gene. We have shown that the alpha gene is controlled by five enhancers which act as an integrated unit which comes into physical proximity with its target gene as it switches it on. By labelling the RNA produced by gene with a fluorescent probe we have recently shown by live imaging, that when activated, the gene is not continuously active but pulses on and off over time. This is a key mechanism underlying the regulation of gene expression. In the current proposal, we are investigating this mechanism and in particular asking if it is regulated by the enhancer. We will do this by comparing the pattern of gene expression with no enhancers and then how this is modified by re-introducing the five enhancers in various informative combinations. Finally, we will test our findings in their clinical context by examining how natural mutations of the human enhancers are correlated with changes in the red cells of affected individuals. By obtaining a complete understanding of gene regulation, we aim to find out how genes are normally switched on and off, how this is perturbed in human genetic disease and how we might use gene editing tools in future to modify and cure such diseases.