1005 – SWITCHING GENES ON AND OFF DURING HAEMATOPOIESIS

We study how transcriptional and epigenetic programmes are played out on chromatin spanning the alpha globin cluster as hematopoietic cells undergo lineage fate decisions and differentiation to form erythroid cells. The alpha globin cluster and its regulatory elements are silenced in early progenitors, poised for expression in later progenitors and fully expressed during terminal erythroid differentiation. Using a variety of approaches we have established the order in which silencing factors are removed, activating transcription factors bind and epigenetic modifications occur. In addition, we have shown how chromosomal conformation and nuclear sub-localisation change during hematopoiesis. Detailed experimental analysis of individual elements is providing insight into the fundamental regulatory elements of the genome. Natural cis and trans acting mutations that cause alpha thalassaemia provide additional insight into how the long-range regulatory elements may interact with the promoters of the globin genes and other flanking genes to activate their expression. Together these observations establish some of the general principles by which genes within their natural chromosomal environment are switched on and off during differentiation and development and how these processes are perturbed in human disease.