Genetics and genomics of GATA-1 function in hematopoiesis.

摘要

GATA-1 is a zinc-finger transcription factor that is specifically expressed in erythroid cells, megakaryocytes, eosinophils, mast cells, and, in addition, in the Sertoli cells of the testis. The tissue-restricted pattern of GATA-1 expression and the presence of consensus DNA sites for GATA-1 binding in the promoters of virtually all erythroid and megakaryocytic genes examined suggest that GATA-1 contributes to lineage-specific gene expression. Here I study GATA-1 function with genetic and genomic approaches. First, I examine the interaction between GATA-1's N-terminal zinc finger and DNA by studying a naturally occurring human mutation in this region of GATA-1, a mutation that co-segregates with an X-linked syndrome of thrombocytopenia with thalassemia. Second, I explore the regulation of GATA-1 itself through deletion of a double GATA-site in the GATA-1 promoter in mice: this leads to the selective loss of the eosinophilic lineage in vivo. Third, I describe the induction and suppression of specific genes in an erythroid cell line that undergoes maturation after activation of GATA-1; using a subtractive screen and DNA microarray analysis, I demonstrate functional groupings of gene expression. These studies of GATA-1 reveal at least three important regulatory mechanisms at work during hematopoiesis: lineage-restricted expression of a transcription factor, differential modulation of gene expression by a single transcription factor via the formation of alternative macromolecular complexes, and coordinate regulation of genes of similar function following transcription factor activation.