Understanding mechanisms of gamma-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction.
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 erythropoiesis 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.
Pace
Betty S
BS
University of Texas at Dallas, Department of Molecular and Cell Biology, Richardson, Texas 75083, USA. bpace@utdallas.edu
Zein
Sima
S
D000755:Anemia, Sickle Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D004920:Erythropoiesis; D005319:Fetal Hemoglobin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005914:Globins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation
D056572:Histone Deacetylase Inhibitors; D005914:Globins; D005319:Fetal Hemoglobin; D015254:DNA Modification Methylases