| The transcription factor GATA-1 and its cofactor FOG-1 are essential for the normal development of erythroid cells and megakaryocytes. FOG-1 can stimulate or inhibit GATA-1 activity depending on cell and promoter context. However, the mechanism(s) by which GATA-1 interacts with FOG-1 to regulate the expression of distinct sets of genes in megakaryocytes and erythroid cells is not well understood. The alphaIIb gene, which encodes the a integrin chain of the platelet-specific fibrinogen receptor alphaIIb/beta3, has long served as a model for understanding the molecular basis of high level, megakaryocyte-specific gene expression. In this thesis, I examined the molecular basis for the megakaryocytes-restricted activation of alphaIIb gene by GATA-1 and FOG-1, providing new insights into a GATA-Ets signature motif found in the promoter regions of alphaIIb gene and other numerous megakaryocytic genes. In addition, I identified Fli-1 as a tissue-specific Ets binding protein that converts FOG-1 from a repressor into a GATA-1 coactivator. The implication of these findings might extend beyond megakaryocyte regulation to the regulation of genes controlled by GATA and FOG proteins in diverse tissues, including erythroid cells, lymphoid cells and the heart. |
