Human γ- To β-globin gene switching in transgenic mice

Previous studies demonstrated correct tissue- and temporal-specific expression of human γ- and β-globin genes in transgenic mice; however, expression was extremely low. When the erythroid-specific DNase I super-hypersensitive (HS) sites that are normally located upstream of the human β-globin locus were fused individually to γ- or β-globin genes, expression increased to endogenous mouse globin levels but temporal specificity was lost. In contrast, when the HS sequences were combined with fragments containing both γ- and β-globin genes, correct developmental regulation was restored. We suggest that human -γ- to β-globin gene switching during development results from competition of individual globin gene family members for interaction with the HS sequences and that factors influencing these competitive interactions determine temporal specificity.