title: Fetal hemoglobin silencing in humans.
abstract: Interruption of the normal fetal-to-adult transition of hemoglobin expression should largely ameliorate sickle cell and beta-thalassemia syndromes. Achievement of this clinical goal requires a robust understanding of gamma-globin gene and protein silencing during human development. For this purpose, age-related changes in globin phenotypes of circulating human erythroid cells were examined from 5 umbilical cords, 99 infants, and 5 adult donors. Unexpectedly, an average of 95% of the cord blood erythrocytes and reticulocytes expressed HbA and the adult beta-globin gene, as well as HbF and the gamma-globin genes. The distribution of hemoglobin and globin gene expression then changed abruptly due to the expansion of cells lacking HbF or gamma-globin mRNA (silenced cells). In adult reticulocytes, less than 5% expressed gamma-globin mRNA. These data are consistent with a "switching" model in humans that initially results largely from gamma- and beta-globin gene coexpression and competition during fetal development. In contrast, early postnatal life is marked by the rapid accumulation of cells that possess undetectable gamma-globin mRNA and HbF. The silencing phenomenon is mediated by a mechanism of cellular replacement. This novel silencing pattern may be important for the development of HbF-enhancing therapies.
authors.affiliation: Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Bldg 10, Rm 9B17, Bethesda, MD 20892, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Oneal
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Gantt
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Schwartz
authors.forename: Natarajan V
authors.initials: NV
authors.lastname: Bhanu
authors.forename: Y Terry
authors.initials: YT
authors.lastname: Lee
authors.forename: John W
authors.initials: JW
authors.lastname: Moroney
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Reed
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
authors.forename: Naomi L C
authors.initials: NL
authors.lastname: Luban
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Miller
mesh_terms: D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood / Q000235:genetics / Q000628:therapy; D005312:Fetal Blood / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D005914:Globins / Q000235:genetics; D006441:Hemoglobin A / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017086:beta-Thalassemia / Q000097:blood / Q000235:genetics / Q000628:therapy
chemical_list: D012333:RNA, Messenger; D005914:Globins; D006441:Hemoglobin A; D005319:Fetal Hemoglobin