Expression and developmental control of the human alpha-globin gene cluster.
The human alpha-globin gene cluster contains three functional genes zeta, alpha 2 and alpha 1. The zeta-globin gene is expressed exclusively in the primitive erythroblasts of the embryonic yolk sac and is selectively silenced during the transition from primitive to definitive erythropoesis. The two alpha-globin genes are expressed through development; they are expressed at equivalent levels in embryonic cells at a 2.6:1 ratio of alpha 2:alpha 1 in fetal and adult cells. The dominant contribution of the alpha 2-globin locus to overall expression of adult alpha-globin is reflected in the more severe phenotype resulting from mutations that affect this locus. Developmental silencing of the zeta-globin gene reflects both transcriptional and posttranscriptional mechanisms. Transcriptional silencing is mediated by an interaction between the zeta-globin gene promoter and a silencer located in the 3' flanking region. This transcriptional silencing is only partial, and residual levels of zeta-globin mRNA are subject to subsequent degredation. This instability of zeta-globin mRNA relative to that of alpha-globin mRNA reflects differences in their respective 3'UTR segments; the zeta-globin mRNA 3'UTR has a lower affinity for a sequence-specific mRNP stability complex which assembles at this site. The alpha-globin mRNA assembles this complex at a higher efficiency and mutations which interfere with 3'UTR function result in corresponding loss of alpha-globin gene expression. These data outline a developmental pathway for the alpha-globin gene cluster which reflects transcriptional and posttranscriptional controls.
Liebhaber
S A
SA
Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia 19104-6148, USA. Steve_L@hmivax.humgen.upenn.edu
Russell
J E
JE
D000328:Adult; D004622:Embryo, Mammalian; D004912:Erythrocytes / Q000378:metabolism; D005333:Fetus; D018507:Gene Expression Regulation, Developmental; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics*; D006801:Humans; D005810:Multigene Family; D012333:RNA, Messenger / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid
D012333:RNA, Messenger; D005914:Globins