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 ex pression, the gamma and beta genes are expressed competitively by an altern ating transcription mechanism. The -50 region of the gamma gene promoter ha s been proposed to be responsible for the early competitive advantage of th e gamma genes and to act as a stage selector element (SSE) in hemoglobin sw itching. We analyzed the effect of mutating the -50 region of the gamma gen e in the presence of a competing beta gene in transgenic mice. This shows t hat the -50 region does not affect silencing of the beta gene in early deve lopment 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 o f fetal development. Interestingly, both the wild-type and mutant minilocus constructs show a higher frequency of alternate transcription than observe d in the complete locus, suggesting that sequences normally present between the gamma and beta genes facilitate the interaction of the locus control r egion (LCR) and beta -globin gene in the complete locus.