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Role of Intergenic Human γ‐δ‐Globin Sequences in Human Hemoglobin Switching and Reactivation of Fetal Hemoglobin in Adult Erythroid Cells
Author(s) -
BANK ARTHUR,
O'NEILL DAVID,
LOPEZ ROCIO,
PULTE DIANNE,
WARD MAUREEN,
MANTHA SIMON,
RICHARDSON CHRISTINE
Publication year - 2005
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1345.057
Subject(s) - intergenic region , globin , biology , hemoglobin , fetal hemoglobin , gene , haematopoiesis , fetus , genetics , microbiology and biotechnology , stem cell , biochemistry , pregnancy , genome
A bstract : 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 γ‐ and δ‐globin genes (intergenic γ‐δ 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 γ‐δ region upstream of the δ 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 γ‐δ 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 δ‐globin gene within the Corfu deletion. Deletion of the PYR binding site has been shown to delay human γ‐to‐β 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 γ‐δ sequences are involved in human γ‐to‐β globin switching and reactivation of fetal hemoglobin in adult cells.