HUMAN GAMMA-GLOBIN GENES SILENCED INDEPENDENTLY OF OTHER GENES IN THE BETA-GLOBIN LOCUS

ERYTHROPOIESIS during human development is characterized by switches in expression of beta-like globin genes during the transition from the embryonic through fetal to adult stages. Activation and high-level expression of the genes is directed by the locus control region (LCR), located 5' to the epsilon-gene 1-3. The location of the LCR and its role in directing high-level expression of the globin genes has led to the suggestion that competition from the beta-gene for interaction with the LCR has a major role in silencing the fetal gamma-genes during adult life 4,5. We have now constructed lines of transgenic mice containing the human A-gamma-globin gene linked to the LCR. We observe high-level expression of the transgene in the embryonic stages but silencing of the gene in adult animals. We conclude that the gamma-gene is not deregulated by the presence of the LCR and that competition from the beta-gene is not required for silencing of the gamma-genes in adult life. The silencing is therefore likely to be mediated by stage-specific factors binding to sequences immediately flanking the genes.