Fetal hemoglobin silencing in humans.
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.
Oneal
Patricia A
PA
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.
Gantt
Nicole M
NM
Schwartz
Joseph D
JD
Bhanu
Natarajan V
NV
Lee
Y Terry
YT
Moroney
John W
JW
Reed
Christopher H
CH
Schechter
Alan N
AN
Luban
Naomi L C
NL
Miller
Jeffery L
JL
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
D012333:RNA, Messenger; D005914:Globins; D006441:Hemoglobin A; D005319:Fetal Hemoglobin