Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells.

The details of the molecular events regulating normal human hemoglobin switching and reactivation of fetal hemoglobin in adult hematopoietic cells are unclear. The potential role of sequences between the human gamma- and delta-globin genes (intergenic gamma-delta sequences) in this process has been in question until the recent finding that two patients homozygous for the Corfu deletion, involving the loss of 7.2 kb of the intergenic gamma-delta region upstream of the delta gene, have 88% and 90% fetal hemoglobin, only mild anemia, and no transfusion requirements. These results provide the first strong evidence in humans that the gamma-delta intergenic sequences alone have a role in the reactivation of fetal hemoglobin in adult-type cells, and perhaps are involved in normal hemoglobin switching as well. The polypyrimidine (PYR) complex is a hematopoietic cell-specific and stage-specific chromatin remodeling complex that binds upstream of the human delta-globin gene within the Corfu deletion. Deletion of the PYR binding site has been shown to delay human gamma-to-beta globin switching. The PYR complex is present in adult human hematopoietic cells and absent in fetal-embryonic cells: properties of a globin-switching complex. Taken together, the data from patients with the Corfu deletion and the PYR complex results suggest that intergenic gamma-delta sequences are involved in human gamma-to-beta globin switching and reactivation of fetal hemoglobin in adult cells.