The analysis of a number of cases of
beta-globin thalassemia and hereditary persistence of
fetal hemoglobin (HPFH) due to large deletions in the
beta-globin locus has led to the identification of several
DNA elements that have been implicated in the switch from human fetal gamma- to adult
beta-globin gene expression. We have tested this hypothesis for an
element that covers the minimal distance between the
thalassemia and HPFH deletions and is thought to be responsible for the difference between a deletion HPFH and deltabeta-
thalassemia, located 5' of the
delta-globin gene. This
element has been deleted from a yeast artificial chromosome (YAC) containing the complete human
beta-globin locus. Analysis of this modified YAC in transgenic mice shows that early embryonic expression is unaffected, but in the fetal liver it is subject to position effects. In addition, the efficiency of transcription of the
beta-globin gene is decreased, but the developmental silencing of the
gamma-globin genes is unaffected by the deletion. These results show that the deleted
element is involved in the activation of the
beta-globin gene perhaps through the loss of a structural function required for gene activation by long-range interactions.