Distinct negative regulatory mechanisms involved in the repression of human embryonic epsilon- and fetal G gamma-globin genes in transgenic mice.

A current model for human beta-globin gene switching proposes that the stage-specific activation of embryonic and fetal globin genes requires the interaction of the beta-globin locus control region with proximal promoter elements. Subsequent repression in fetal and adult stages likely involves negative regulatory promoter elements and factors. To begin addressing these negative regulatory mechanisms, the regulation of human fetal G gamma-globin promoter fused to the SV40 T antigen gene was analyzed in transgenic mice. The results showed correct developmental expression in erythroid tissue, but lower levels of expression were also detected in non-erythroid tissue. Thus, the 5'-flanking G gamma-globin promoter sequence contains stage-specific erythroid elements but is lacking nonerythroid-specific negative elements. In contrast, the human embryonic epsilon-globin gene was only expressed in nonerythroid tissue of transgenic embryos, suggesting the presence of an erythroid-specific negative element(s). With the locus control region, complete repression of epsilon-globin RNA in fetal liver was observed in epsilon-globin genes without the previously characterized silencer, suggesting the presence of additional negative elements. Overall, this transgenic study suggests that distinct negative regulatory mechanisms function in the repression of embryonic and fetal globin genes.