The mechanisms underlying the human fetal-to-adult beta-globin gene switch 
remain to be determined. While there is substantial experimental evidence to 
suggest that promoter DNA methylation is involved in this process, most data 
come from studies in nonhuman systems. We have evaluated human gamma- and 
beta-globin promoter methylation in primary human fetal liver (FL) and adult 
bone marrow (ABM) erythroid cells. Our results show that, in general, promoter 
methylation and gene expression are inversely related. However, CpGs at -162 of 
the gamma promoter and -126 of the beta promoter are hypomethylated in ABM and 
FL, respectively. We also studied gamma-globin promoter methylation during in 
vitro differentiation of erythroid cells. The gamma promoters are initially 
hypermethylated in CD34(+) cells. The upstream gamma promoter CpGs become 
hypomethylated during the preerythroid phase of differentiation and are then 
remethylated later, during erythropoiesis. The period of promoter 
hypomethylation correlates with transient gamma-globin gene expression and may 
explain the previously observed fetal hemoglobin production that occurs during 
early adult erythropoiesis. These results provide the first comprehensive survey 
of developmental changes in human gamma- and beta-globin promoter methylation 
and support the hypothesis that promoter methylation plays a role in human 
beta-globin locus gene switching.