Switching Genes On and Off During Hematopoiesis.

We have studied how transcriptional and epigenetic programs are played out on chromatin spanning the terminal 500kb of human chromosome 16 (16p13.3) as hematopoietic cells undergo lineage fate decisions and differentiation. This region includes the alpha globin cluster and its regulatory elements, which are silenced in early progenitors, poised for expression in later progenitors, and fully expressed during terminal erythroid differentiation. Other genes in this region are also upregulated in an erythroid specific manner. 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 sublocalization change during hematopoiesis. 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 hematopoiesis.