• fetal hemoglobin;
  • sickle cell disease;
  • histone deacetylase inhibitors;
  • decitabine;
  • hydroxyurea;
  • short chain fatty acids;
  • p38 MAPK;
  • cGMP


The developmental regulation of γ-globin gene expression has shaped research efforts to establish therapeutic modalities for individuals affected with sickle cell disease (SCD). Fetal hemoglobin (Hb F) synthesis is high at birth, followed by a decline to adult levels by 10 months of age. The expression of γ-globin is controlled by a developmentally regulated transcriptional program that is recapitulated during normal erythropoiesis in the adult bone marrow. It is known that naturally occurring mutations in the γ-gene promoters cause persistent Hb F synthesis after birth, which ameliorates symptoms in SCD by inhibiting hemoglobin S polymerization and vaso-occlusion. Several pharmacological agents have been identified over the past 2 decades that reactivate γ-gene transcription through different cellular systems. We will review the progress made in our understanding of molecular mechanisms that control γ-globin expression and insights gained from Hb F–inducing agents that act through signal transduction pathways. Developmental Dynamics 235:1727–1737, 2006. © 2006 Wiley-Liss, Inc.