Schematic model of cell type–specific and inducible Epo gene regulation by GATA factors. (A) Epo gene expression is controlled by cell type–specific and hypoxia-inducible enhancers. Both enhancers are required for inducible Epo gene expression in REP cells and hepatocytes. (B) In the epithelial cell lineage, the epithelial cell–specific enhancer constitutively stimulates Epo gene expression, but this is repressed through the GATA promoter motif. Therefore, epithelial cells do not express Epo, in spite of hypoxic conditions. (C) In other cell types, Epo expression may be permanently silenced by epigenetic mechanisms unrelated to GATA repression and the hypoxic threshold.