Fetal hemoglobin silencing in humans

Patricia A. Oneal, Nicole M. Gantt, Joseph D. Schwartz, Natarajan V. Bhanu, Y. Terry Lee, John W. Moroney, Christopher H. Reed, Alan N. Schechter, Naomi L.C. Luban, Jeffery L. Miller

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


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.

Original languageEnglish
Pages (from-to)2081-2086
Number of pages6
Issue number6
StatePublished - 15 Sep 2006


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