LIGAND-DEPENDENT REPRESSION OF THE ERYTHROID TRANSCRIPTION FACTOR GATA-1 BY THE ESTROGEN-RECEPTOR

High-dose estrogen administration induces anemia in mammals, In chicke ns, estrogens stimulate outgrowth of bone marrow-derived erythroid pro genitor cells and delay their maturation, This delay is associated wit h down-regulation of many erythroid cell-specific genes, including alp ha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5, We show here that estrogens also reduce the number of ery throid progenitor cells in primary human bone marrow cultures, To addr ess potential mechanisms by which estrogens suppress erythropoiesis, w e have examined their effects on GATA-1, an erythroid transcription fa ctor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocyt es. We demonstrate that the transcriptional activity of GATA-1 is stro ngly repressed by the estrogen receptor (ER) in a ligand-dependent man ner and that this repression is reversible in the presence of 4-hydrox ytamoxifen, ER-mediated repression of GATA-1 activity occurs on an art ificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA- 1, GATA-1 and ER bind to each other in vitro in the absence of DNA, In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner, Mapping experiments in dicate that GATA-1 and the ER form at least two contacts, which involv e the finger region and the N-terminal activation domain of GATA-1, We speculate that estrogens exert effects on erythropoiesis by modulatin g GATA-1 activity through protein-protein interaction with the ER. Int erference with GATA-binding proteins may be one mechanism by which ste roid hormones modulate cellular differentiation.