The regulation of the embryonically expressed zeta-globin gene
α-thalassaemia is a haemoglobinopathy resulting from the impaired production of α-globin that occurs most frequently from deletions of the paralogous α-globin genes (HBA1 & HBA2). Homozygous deletion of these genes is termed α0-thalassaemia and causes lethal neonatal anaemia called Hb Barts’ Hydrops Fetalis Syndrome (BHFS). The most common cause of α0-thalassaemia is a 20.5-kb deletion termed the South East Asian (SEA) deletion, which leaves the embryonically expressed ζ-globin gene (HBZ) intact and available for reactivation. Reactivating HBZ is, therefore, a potential therapeutic strategy to ameliorate the severe symptoms of α-thalassaemia. Separately, the silencing of the ζ-globin gene poses an important question in gene regulation as it lies immediately adjacent to the highly active α-globin enhancers and yet remains transcriptionally inactive in definitive erythroid cells. The silencing mechanism is poorly understood yet is of great interest as it is likely to be widely applicable.
The core question I am addressing is determining the mechanism by which the embryonically expressed ζ-globin gene is silenced in adult erythroblasts and how it may be reactivated in patients with severe α-thalassaemia.