Journal
DEVELOPMENTAL DYNAMICS
Volume 235, Issue 7, Pages 1727-1737Publisher
WILEY
DOI: 10.1002/dvdy.20802
Keywords
fetal hemoglobin; sickle cell disease; histone deacetylase inhibitors; decitabine; hydroxyurea; short chain fatty acids; p38 MAPK; cGMP
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Funding
- NHLBI NIH HHS [HL69234, HL073447] Funding Source: Medline
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The developmental regulation of gamma-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 gamma-globin is controlled by a developmentally regulated transcriptional program that is recapitulated during normal crythropoiesis in the adult bone marrow. It is known that naturally occurring mutations in the gamma-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 gamma-gene transcription through different cellular systems. We will review the progress made in our understanding of molecular mechanisms that control gamma-globin expression and insights gained from Hb F-inducing agents that act through signal transduction pathways.
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