Understanding mechanisms of γ-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction

Betty S. Pace, Sima Zein

Research output: Contribution to journalReview article

41 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1727-1737
Number of pages11
JournalDevelopmental Dynamics
Volume235
Issue number7
DOIs
StatePublished - Jul 1 2006
Externally publishedYes

Keywords

  • Decitabine
  • Fetal hemoglobin
  • Histone deacetylase inhibitors
  • Hydroxyurea
  • Short chain fatty acids
  • Sickle cell disease
  • cGMP
  • p38 MAPK

ASJC Scopus subject areas

  • Developmental Biology

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