Abstract
Activation of γ-globin gene expression in adults is known to be therapeutic for sickle cell disease. Thus, it follows that the converse, alleviation of repression, would be equally effective, since the net result would be the same: an increase in fetal hemoglobin. A GATA-1-FOG-1-Mi2 repressor complex was recently demonstrated to be recruited to the −566 GATA motif of the Aγ-globin gene. We show that Mi2β is essential for γ-globin gene silencing using Mi2β conditional knockout β-YAC transgenic mice. In addition, increased expression of Aγ-globin was detected in adult blood from β-YAC transgenic mice containing a T>G HPFH point mutation at the −566 GATA silencer site. ChIP experiments demonstrated that GATA-1 is recruited to this silencer at day E16, followed by recruitment of FOG-1 and Mi2 at day E17 in wild-type β-YAC transgenic mice. Recruitment of the GATA-1–mediated repressor complex was disrupted by the −566 HPFH mutation at developmental stages when it normally binds. Our data suggest that a temporal repression mechanism is operative in the silencing of γ-globin gene expression and that either a trans-acting Mi2β knockout deletion mutation or the cis-acting −566 Aγ-globin HPFH point mutation disrupts establishment of repression, resulting in continued γ-globin gene transcription during adult definitive erythropoiesis.
Highlights
The human b-globin locus is composed of five functional genes (e, Gc, Ac, d, and b) and a master regulatory region called the locus control region (LCR)
An understanding of the mechanisms that regulate the globin gene switching is of fundamental importance, since reactivation of the fetal hemoglobin expression during definitive erythropoiesis is well-established as therapeutic for hemoglobinopathies such as sickle cell disease (SCD) and b-thalassemias
Scientific evidence has demonstrated that continued expression of the fetal c-globin genes, which are normally silenced after birth, is the best treatment for SCD, since the pathophysiology is largely ameliorated
Summary
The human b-globin locus is composed of five functional genes (e, Gc, Ac, d, and b) and a master regulatory region called the locus control region (LCR). These genes are arrayed in the order in which they are progressively expressed during development. The second switch is from the fetal c-globins in the liver to the adult globins (mostly b-globin, with d-globin as a minor component) in the bone marrow This switch is characterized by the progressive silencing of the c-globin genes, with the concomitant activation of b-globin gene expression, and is not completed until after birth. An understanding of the mechanisms that regulate the globin gene switching is of fundamental importance, since reactivation of the fetal hemoglobin expression during definitive erythropoiesis is well-established as therapeutic for hemoglobinopathies such as sickle cell disease (SCD) and b-thalassemias
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