DEVELOPMENTAL SILENCING OF THE EMBRYONIC ZETA-GLOBIN GENE - CONCERTEDACTION OF THE PROMOTER AND THE 3'-FLANKING REGION COMBINED WITH STAGE-SPECIFIC SILENCING BY THE TRANSCRIBED SEGMENT

Globin gene switching is a well-described model of eucaryotic developm ental control. In the case of the human alpha-globin gene cluster, mig ration of erythropoietic activity from the embryonic yolk sac to the f etal liver is paralleled by zeta-globin gene silencing and enhanced ex pression of the alpha-globin genes. To map critical cir determinants o f this switch, the human zeta-globin gene, the alpha-globin gene, and chimeric recombinants were introduced into the mouse genome. Consisten t with previous studies, expression of the individual alpha- and zeta- globin transgenes was found to be developmentally appropriate. Contrar y to current models, however, the alpha- and zeta-globin gene promoter s were not sufficient to establish this control. Instead, full silenci ng of the zeta-globin gene required the combined activities of its pro moter, transcribed region, and 3'-flanking sequences. Individually, th e silencing activities of the zeta-globin gene promoter and 3'-flankin g region were minimal but increased markedly when both regions were pr esent. The zeta-globin transcribed region appeared to contribute to ge ne silencing by a mechanism specifically activated in definitive eryth roblasts in the fetal liver. These data demonstrate that a complex set of controls, requiring at least three determinants and involving at l east two independent mechanisms, is necessary for full developmental s ilencing of the human zeta-globin gene.