Developmental silencing of the embryonic zeta-globin gene: concerted action 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 developmental control. In the case of the human alpha-globin gene cluster, migration of erythropoietic activity from the embryonic yolk sac to the fetal liver is parallaled by the zeta-globin gene silencing and enhanced expression of the alpha-globin genes. To map critical cis determinants of this switch, the human zeta-globin gene, the alpha-globin gene, and chimeric recombinants were introduced into the mouse genome. Consistent with previous studies, expression of the individual alpha- and zeta-globin transgenes was found to be developmentally appropriate. Contrary to current models, however, the alpha- and zeta-globin gene promoters were not sufficient to establish this control. Instead, full silencing of the zeta-globin gene required the combined activities of this promoter, transcribed region, and 3'-flanking sequences. Individually, the silencing activities of the zeta-globin gene promoter and 3'-flanking region were minimal but increased markedly when both regions were present. The zeta-globin transcribed region appeared to contribute to gene silencing by a mechanism specifically activated in definitive erythroblasts in the fetal liver. These data demonstrate that a complex set of controls, requiring at least three determinants and involving at least two independent mechanisms, is necessary for full developmental silencing of the human zeta-globin gene.
Liebhaber
S A
SA
Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.
Wang
Z
Z
Cash
F E
FE
Monks
B
B
Russell
J E
JE
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002465:Cell Movement; D005314:Embryonic and Fetal Development / Q000235:genetics; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D015017:Yolk Sac / Q000378:metabolism
D005914:Globins