A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells

Natarajan V. Bhanu, Tiffany A. Trice, Y. Terry Lee, Nicole M. Gantt, Patricia Oneal, Joseph D. Schwartz, Pierre Noel, Jeffery L. Miller

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

We systematically compared cytokine-mediated increases or decreases in proliferation with globin gene and protein expression in adult human erythroblasts. Despite their opposite effects on growth, stem cell factor (SCF) and transforming growth factor-beta (TGF-B) had synergistic effects with respect to fetal hemoglobin (HbF): average HbF/HbF + adult hemoglobin (HbA) ratio in erythropoietin (EPO) = 1.4 ± 1.0%; EPO + TGF-B = 10.8 ± 1.9%; EPO + SCF = 19.1 ± 6.2%; and EPO + SCF + TGF-B (EST) = 39.3 ± 6.3%. Polymerase chain reaction (PCR) revealed significant increases in gamma-globin transcripts that were balanced by reduced beta-globin transcripts. Single-cell quantitative PCR demonstrated a complete reversal of gamma-globin gene silencing with detectable gamma-globin mRNA in more than 95% of the cells. Immunostaining with HbF antibodies also showed a pancellular distribution in EST (96.2 ± 0.01% HbF positive) compared with a heterocellular distribution in EPO (42.9 ± 0.01% HbF positive). As shown here for the first time, a robust and pancellular reversal of gamma-globin gene silencing among hemoglobinized erythroblasts from adult humans may be achieved in the absence of hereditary mutation or direct genomic manipulation.

Original languageEnglish (US)
Pages (from-to)387-393
Number of pages7
JournalBlood
Volume105
Issue number1
DOIs
StatePublished - Jan 1 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Bhanu, N. V., Trice, T. A., Lee, Y. T., Gantt, N. M., Oneal, P., Schwartz, J. D., Noel, P., & Miller, J. L. (2005). A sustained and pancellular reversal of gamma-globin gene silencing in adult human erythroid precursor cells. Blood, 105(1), 387-393. https://doi.org/10.1182/blood-2004-04-1599