Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1

The process through which multipotential hematopoietic cells commit to dist inct lineages involves the induction of specific transcription factors. PU. 1 (also known as Spi-1) and GATA-1 are transcription factors essential for the development of myeloid and erythroid lineages, respectively. Overexpres sion of PU.1 and GATA-1 can block differentiation in lineages in which they normally are down-regulated, indicating that not only positive but negativ e regulation of these factors plays a role in normal hematopoietic lineage development. Here we demonstrate that a region of the PU.1 Ets domain (the winged helix-turn-helix wing) interacts with the conserved carboxyl-termina l zinc finger of GATA-1 and GATA-2 and that GATA proteins inhibit PU.1 tran sactivation of critical myeloid target genes. We demonstrate further that G ATA inhibits binding of PU.1 to c-Jun, a critical coactivator of PU.1 trans activation of myeloid promoters. Finally, PU.1 protein can inhibit both GAT A-1 and GATA-2 transactivation function. Our results suggest that interacti ons between PU.1 and GATA proteins play a critical role in the decision of stem cells to commit to erythroid vs. myeloid lineages.