Mi2β Is Required for γ-Globin Gene Silencing: Temporal Assembly of a GATA-1-FOG-1-Mi2 Repressor Complex in β-YAC Transgenic Mice

Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
PLoS Genetics (Impact Factor: 7.53). 12/2012; 8(12):e1003155. DOI: 10.1371/journal.pgen.1003155
Source: PubMed


Author Summary
Sickle cell disease (SCD) is one of the most common genetic diseases, affecting millions of people worldwide. SCD affects red blood cells' shape and renders them ineffective, resulting in anemia along with attendant complications. The disease is caused by a single point mutation in the coding sequence of the adult β-globin gene that changes normal adult hemoglobin (HbA) to sickle hemoglobin (HbS). Scientific evidence has demonstrated that continued expression of the fetal γ-globin genes (fetal hemoglobin, HbF), which are normally silenced after birth, is the best treatment for SCD, since the pathophysiology is largely ameliorated. Our therapeutic goal is to reactivate the γ-globin genes to substitute for the defective adult β-globin gene. We identified a novel γ-globin gene silencer sequence and demonstrated that a GATA-1-FOG-1-Mi2 repressor complex binds to this sequence and silences γ-globin synthesis. However, data regarding the requirement of Mi2 for silencing is controversial. We demonstrate that γ-globin synthesis increases as Mi2 expression decreases. We also show that repressor complex components assemble sequentially during development; completion of assembly coincides with γ-globin gene silencing. Disruption of either the repressor complex or mutation of its binding site induces γ-globin. Understanding this mechanism will reveal potential new targets for treating SCD.

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