Globin genes exhibit tissue, developmental and maturational specificity. It is our purpose to understand the molecular basis of globin gene regulation. Our efforts have focused on the beta-globin gene cluster that contains the epsilon, gamma and beta genes expressed during the embryonic, fetal and adult developmental periods, respectively. These genes are encompassed within a 60 kilobase segment of DNA on human chromosome II. Within this cluster are several cis-acting regulatory elements that interact with transacting factors (proteins) to modulate globin gene expression. Our efforts have focused on three such regulatory elements. The locus activating region (LAR) located upstream from the cluster establishes erythroid specificity of expression. Four separate regulatory elements have been identified within the LAR. We have characterized a 20 base pair segment within one of these elements that functions as a very powerful enhancer. This enhancer is responsible for the increase in globin gene expression that occurs during erythroid maturation. It binds members of the AP-1 family including JUN and FOS species. However, its ability to augment hemoglobin synthesis during differentiation relies on its binding of an erythroid specific nuclear protein, NF-E2. The enhancer 3' to the gamma globin gene and the upstream region of the gamma globin gene promoter have also been characterized. These sequences are involved in gene regulation during development. A complex of proteins have been shown to bind to related sequences in the two elements. One of these proteins may be fetal stage specific and thus could participate in the developmental switch. Our efforts are now focused on purification of these two proteins that may be particularly relevant to the developmental specificity of globin gene expression in erythroid cells.
