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Molecular Control of Erythropoiesis

Final Activity Report Summary - EURYTHRON (Molecular control of erythropoiesis)

A healthy organism is the product of a highly orchestrated, complex series of gene activities within cells and tissues. Errors result in ageing, cell death and disease. Since blood carries essential oxygen to all tissues of the body, understanding how blood functions is vital for survival of the organism. The study of gene activity is facilitated by isolation and purification of the gene, and the red cells of the blood have done this for us because globin genes represent a high percentage of the total gene activity within the red cell. Thus globin is an excellent model for studying gene action at the molecular level in higher organisms. The high incidence of blood diseases including leukaemias (the commonest cancers in man) further underlines the importance of understanding blood functions. Unlike other tissues, blood self renews approximately every 100 days, starting with a stem cell located in the bone marrow via a number of progenitor stages to the fully differentiated red and white blood cells circulating through our vessels. Blood, therefore, has become a paradigm for investigating the many steps from stem cell to fully differentiated cell types, and the haematopoietic stem cell (HSC), studied for over 50 years, represents the best understood of all stem cells in the body. It is against this background that the EURYTHRON project was conceived.

The collaborative efforts of the project have produced many significant advances. GATA2 is an important gene whose protein product controls the fate of early blood progenitors and exciting studies are in progress identifying protein partners and DNA binding sites on a genome wide level of analysis. Viruses can help us introduce genes into cells. Viral introduction of a fluorescent marker into mouse embryo HSCs has allowed us, for the first time, to confirm the identity of the earliest stem cells and to follow their development. We are developing novel methods to convert more accessible non-blood cells into HSCs using viral introduction of proteins known to be pivotal for blood development with the ultimate aim of avoiding the difficulties involved in bone marrow transplantation. The consortium has obtained new molecular insights into the anaemias DBA and SBDA. Additionally, the gene BMI1 has been identified as a target for treatment of chronic myeloid leukaemia and a novel transplantation model has been developed to study its function in stem cells. DNA elements controlling one gene often lie buried within an unrelated gene. We now have insight into how this works that addresses a general issue concerning the relationship between genome structure and function.

We have identified a novel protein, CHOP, which is a positive regulator of red cell development, particularly under stress, and is also needed for maturation of white blood cells. Sophisticated studies in zebrafish show that blood flow is needed for maintenance of HSCs but is not required for their emergence. Also, the signals required for induction of the very earliest stem cells in the embryo have been identified. We have evidence showing that low level radiation accelerates ageing in red cells and that receptors on red cell surfaces interact to link erythropoiesis to iron metabolism. Intricate molecular imaging has generated new visions into nuclear architecture during cellular reprogramming in progenitor cells. Furthermore, a computational approach to a global view of control and surveillance of errors in transcribing DNA into mRNA has been established. Finally, a role for the protein GATA1 in antigen presentation, with possible pharmaceutical potential, is described along with characterisation of protein factors that control GATA1 expression in immature and mature blood cells.

EURYTHRON works via training young scientists under the supervision of established experts in the field. The success of this highly collaborative, interactive group has resulted in a new wave of excellently trained young scientists for the future.