The role of the -50 region of the human gamma-globin gene in switching.
During the switch from human gamma- (fetal) to beta- (adult) globin gene expression, the gamma and beta genes are expressed competitively by an alternating transcription mechanism. The -50 region of the gamma gene promoter has been proposed to be responsible for the early competitive advantage of the gamma genes and to act as a stage selector element (SSE) in hemoglobin switching. We analyzed the effect of mutating the -50 region of the gamma gene in the presence of a competing beta gene in transgenic mice. This shows that the -50 region does not affect silencing of the beta gene in early development and does not act as a stage selector. However, it affects the ratio of gamma versus beta gene expression in the early, but not later, stages of fetal development. Interestingly, both the wild-type and mutant minilocus constructs show a higher frequency of alternate transcription than observed in the complete locus, suggesting that sequences normally present between the gamma and beta genes facilitate the interaction of the locus control region (LCR) and beta-globin gene in the complete locus.
Ristaldi
M S
MS
Department of Cell Biology and Genetics, Erasmus University, Rotterdam, The Netherlands.
Drabek
D
D
Gribnau
J
J
Poddie
D
D
Yannoutsous
N
N
Cao
A
A
Grosveld
F
F
Imam
A M
AM
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005914:Globins / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007700:Kinetics; D051741:Kruppel-Like Transcription Factors; D008099:Liver / Q000196:embryology / Q000378:metabolism; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; C080774:erythroid Kruppel-like factor; D004004:Dichlororibofuranosylbenzimidazole; D005914:Globins