The role of the -50 region of the human γ-globin gene in switching

Abstract

During the switch from human γ- (fetal) to β- (adult) globin gene expression, the γ and β genes are expressed competitively by an alternating transcription mechanism. The -50 region of the γ gene promoter has been proposed to be responsible for the early competitive advantage of the γ genes and to act as a stage selector element (SSE) in hemoglobin switching. We analyzed the effect of mutating the -50 region of the γ gene in the presence of a competing β gene in transgenic mice. This shows that the -50 region does not affect silencing of the β gene in early development and does not act as a stage selector. However, it affects the ratio of γ versus β 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 γ and β genes facilitate the interaction of the locus control region (LCR) and β-globin gene in the complete locus.