Levels of GATA-1/GATA-2 transcription factors modulate expression of embryonic and fetal hemoglobins

GATA transcription factors bind the consensus sequence WGATAR, present in t he flanking regions of most erythroid specific genes. GATA-1 and GATA-2, co expressed in erythroid cells, are important for expression of erythroid gen es. To elucidate the role of specific GATA transcription factors on globin gene expression, we examined the human alpha- and beta -globin gene cluster s for all GATA sites. Conserved GATA sites were found in each of the hypers ensitive sites in both beta -and alpha clusters and in proximal regulatory regions of the zeta-, epsilon- and gamma -globin but not the alpha, delta o r beta -globin genes. We then tested the effect of increasing levels of GAT A-1 and GATA-2 on the expression of endogenous globin genes in human erythr oid cells. Increasing GATA-1 levels in K562 cells decreased the levels of e psilon -globin mRNA but had no effect on the levels of expression of gamma, zeta or alpha -globin genes. Increasing GATA-2 levels increased epsilon -g lobin and gamma -globin transcripts. Increasing levels of GATA-1 also cause d a decrease in the expression of endogenous GATA-2, while increased levels of GATA-2 had no effect on GATA-1 mRNA. Our results indicate a differentia l role of GATA-1 and -2 transcription factors on globin transcripts and sug gest a correlation between the conservation of GATA sites in the regulatory regions and the ability of endogenous globin genes to respond to GATA tran scription factors. They also suggest that quantitative changes in the level s of GATA-1 or GATA-2 can result in alterations of globin target gene expre ssion and may participate in the ontogenic control of the globin genes. (C) 2000 Elsevier Science B.V. All rights reserved.