Transcriptional Regulation of GATA-1

A common cause of severe anaemia that can progress to leukaemia is known as myelodysplasia. In this condition blood cell precursors are made but fail to mature properly and do not function appropriately. Understanding this disorder depends on knowing how blood cells are normally made and mature in the bone marrow.||Our interest has focused on one critical factor that is required in this process, which is called GATA-1. GATA-1 co-ordinates many aspects of the normal maturation programme of blood and we wish to aspects of it biology.

A key biological question, relevant to all differentiating tissues, is how multiple cell types arise from a pluripotential cell. When this process is perturbed it leads to human disease. We are using the haemopoietic system to study this question as it provides a good scientific and clinical model. Our laboratory is focused on how the erythroid and megakaryocytic lineages are specified and mature from a progenitor cell. Our particular interest is the role key transcription factors play in these processes. In particular, the zinc-finger transcription factor GATA-1 is absolutely required for the proper maturation of both the red cell and megakaryocyte lineages. In addition, GATA-1 expression is initiated in early haematopoietic progenitor at low level but then is restricted to principally erythroid and megakaryocytic cells where it is expressed at high level.||Our aim is to understand the molecular mechanisms that result in the tissue- and developmental- specific pattern of expression. As a consequence of these studies we hope to identify the transcriptional regulators that lie upstream of GATA-1 and thus help to specify the erythroid and megakaryocyte lineages.||Our approach to this problem is to try and identify all the cis-acting elements that are required for GATA-1 expression and the trans-acting factors that bind to them. We are identifying putative cis-elements in the GATA-1 locus by DNase I hypersensitivity analysis and by pin-pointing non-coding sequence that is conserved in evolution between mouse and human. Once putative cis-elements have been identified we are testing if they have function in stable cell transfection assays and in transgenic mice. Protein-DNA interactions at functionally important elements will be then be determined. Lastly, the functional importance of selected elements will be further examined by deleting them by homologous recombination in mice.