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Understanding mechanisms of γ‐globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction
Author(s) -
Pace Betty S.,
Zein Sima
Publication year - 2006
Publication title -
developmental dynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.634
H-Index - 141
eISSN - 1097-0177
pISSN - 1058-8388
DOI - 10.1002/dvdy.20802
Subject(s) - fetal hemoglobin , biology , erythropoiesis , globin , gene expression , gene , regulation of gene expression , signal transduction , fetus , transcription (linguistics) , microbiology and biotechnology , genetics , anemia , medicine , pregnancy , linguistics , philosophy
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. Developmental Dynamics 235:1727–1737, 2006. © 2006 Wiley‐Liss, Inc.