I am interested in understanding how genes are switched on and off in single cells, and how this changes during cellular differentiation. To do this, I am using a range of microscopy methods to explore these processes in single living cells.
Understanding the mechanisms by which genes are regulated is fundamentally important to building a more comprehensive model of cell biology. Studies from our lab and others have shown that genes are typically controlled by ‘enhancers’, short DNA sequences situated away from the genes that they regulate which can boost gene activity by recruiting the necessary factors for transcription to occur. Recent studies suggest that despite being far away on the linear genome, these elements can come into contact with gene promoters by looping out the intervening DNA sequence. However, the majority of these studies have used experiments requiring thousands to millions of cells, and therefore represent an average picture of the underlying biology. Complementary approaches, such as microscopy, are needed to more precisely understand how enhancers function to regulate genes in individual cells.
α-globin represents a model gene for studying transcription during differentiation: the gene becomes switched on as cells move along the red blood cell lineage, and this process is controlled by a cluster of regulatory enhancer elements. I am using microscopy techniques to probe the real-time changes in transcriptional output of this gene in living cells at different stages of blood cell development. By simultaneously monitoring the position of the enhancers during this process we will gain a clearer picture of the mechanisms by which enhancer-promoter communication influences transcription.