Submitted December 22, 2005
Accepted May 8, 2006
Fetal hemoglobin silencing in humans
Patricia A Oneal, Nicole M Gantt, Joseph D Schwartz, Natarajan V Bhanu, Y T Lee, John W Moroney, Christopher H Reed, Alan N Schechter, Naomi L Luban, and Jeffery L Miller*
National Institutes of Diabetes, Digestive & Kidney Diseases, National Institutes of Health, MD, USA
Department of Obstetrics & Gynecology, National Naval Medical Center, Bethesda, MD, USA
Laboratory Medicine and Pathology, Children's National Medical Center, Washington, DC, USA
* Corresponding author; email: jm7f{at}nih.gov.
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
(HbF/gamma-globin silenced cells). In adult reticulocytes,
less than 5% expressed gamma-globin mRNA. These data are
consistent with a " switching" model in humans
that initially largely results from gamma- and beta-globin
gene co-expression and competition during fetal
development. In contrast, early post-natal 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.
