How is expression of the embryonic zeta-globin gene regulated in erythropoiesis?

The haemoglobin protein complex is essential for life because it transports oxygen around our bodies. Haemoglobin consists of alpha-globin protein, beta-globin protein and iron. Maintaining an equal ratio of alpha- to beta-globin protein in terminally differentiating erythroblasts is crucial for the normal production of red blood cells. Disorders of haemoglobin result from insufficient production of either the alpha- or beta-globin chains, causing an imbalance in the ratio of alpha- to beta-globin. This leads to production of small, under-haemoglobinised red-cells and ineffective erythropoiesis. At least 340,000 babies with severe genetic disorders of haemoglobin are born each year. Of these ~70,000 suffer from deficiency of the alpha- or beta-globin proteins. These are the most common single gene disorders known, with a carrier rate of >1% among all tropical and subtropical populations studied. Population dynamics mean this is now a global health problem.
The most common cause of alpha-globin insufficiency is deletion of the alpha-globin genes. Children with the most severe symptoms suffer from anaemia with associated tiredness, breathlessness and fatigue, a large spleen (which can be painful), jaundice, growth retardation and many require blood transfusions. Other complications include infections, leg ulcers, gall stones and folic acid deficiency. In later life, the majority of severely affected patients (~85%) have iron overload, which can lead to cirrhosis of the liver and heart problems. The critical point for this study is that, in healthy individuals, and the vast majority of patients with alpha-globin deficiency, there is an alternative alpha-globin gene, termed zeta-globin. However, the zeta-globin gene is normally active only in very early development. The aim of this work is to characterise the mechanisms by which zeta-globin is normally silenced and leverage this information to find novel ways of re-expressing it in patients. Achieving zeta-globin reactivation would re-establish the important balance of alpha- to beta- globin proteins in the blood. This precision medicine would cure the primary problem of anaemia for individuals with severe alpha-thalassemia and its attendant complications, removing the need for blood transfusion and improving their quality of life.
To understand how zeta-globin is normally repressed, this project will provide training in a variety of advanced molecular biology and quantitative bioinformatic techniques. Cell culture and genome engineering will be used to create cell models that test the effects of protein factors and gene regulatory elements on zeta-globin gene expression. These models will be examined with cutting-edge genomic, transcriptomic and microscopy assays and these data will be analysed using appropriate computational approaches. This project was born out of an existing collaboration with partners in industry and has potential for forming new collaborations in future.