In addition to providing insight into the developmental regulation of eukaryotic gene expression, studies of the human gamma globin gene may also suggest means by which these genes, which are normally inactive in adult life, could be reactivated in individuals with disorders of the adult beta globin gene. This laboratory has undertaken a number of projects to analyze the molecular behavior of the human gamma globin genes in response to both cis and trans-acting factors. Studies of a tissue specific cis acting element located just 3' to the A gamma gene have been shown that this fragment has all the properties of an enhancer element and that it may have a role in the regulation of the gamma genes. To study both cis and trans-acting factors during hemoglobin switching, three lines of transgenic mice have been generated carrying 4-8 copies of a construct, consisting of an A gamma gene linked to a human beta globin gene. Several laboratories have demonstrated that point mutations in the gamma promoter (usually in the region approximately 200 bp upstream from the CAP site) are associated with hereditary persistence of fetal hemoglobin (HPFH), implying that this region is a target for trans acting factors in erythroid cells. Deletion analysis of the gamma promoter performed in this laboratory have shown that normal expression of the gamma gene requires the presence of this region. Mutation within this region can increase transcription dramatically, but the only mutations that are effective are those that are associated with HPFH.
