title: Role of intergenic human gamma-delta-globin sequences in human hemoglobin switching and reactivation of fetal hemoglobin in adult erythroid cells.
abstract: 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.
authors.affiliation: Department of Medicine, Columbia University, 701 West 168th St., Rm. 1604, New York, NY 10032, USA. ab13@columbia.edu
authors.forename: Arthur
authors.initials: A
authors.lastname: Bank
authors.forename: David
authors.initials: D
authors.lastname: O'Neill
authors.forename: Rocio
authors.initials: R
authors.lastname: Lopez
authors.forename: Dianne
authors.initials: D
authors.lastname: Pulte
authors.forename: Maureen
authors.initials: M
authors.lastname: Ward
authors.forename: Simon
authors.initials: S
authors.lastname: Mantha
authors.forename: Christine
authors.initials: C
authors.lastname: Richardson
mesh_terms: D000328:Adult; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D002843:Chromatin / Q000235:genetics / Q000648:ultrastructure; D021901:DNA, Intergenic / Q000235:genetics*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism; D005312:Fetal Blood / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005914:Globins / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006801:Humans; D051740:Ikaros Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D012045:Regulatory Sequences, Nucleic Acid; D017384:Sequence Deletion; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002087:Butyrates; D002843:Chromatin; D021901:DNA, Intergenic; D056572:Histone Deacetylase Inhibitors; D046911:Macromolecular Substances; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D005914:Globins; D005319:Fetal Hemoglobin; D006655:Histone Deacetylases