Expression of fetal γ-
globin in adulthood ameliorates symptoms of β-
hemoglobinopathies by compensating for the mutant β-
globin. Reactivation of the silenced γ-
globin gene is therefore of substantial clinical interest. To study the regulation of γ-
globin expression, we created the GG mice, which carry an intact 183-kb human β-
globin locus modified to express
enhanced green fluorescent protein (eGFP) from the Gγ-
globin promoter. GG embryos express eGFP first in the yolk sac blood islands and then in the aorta-gonad mesonephros and the fetal liver, the sites of normal embryonic hematopoiesis. eGFP expression in erythroid cells peaks at E9.5 and then is rapidly silenced (>95%) and maintained at low levels into adulthood, demonstrating appropriate developmental regulation of the human β-
globin locus. In vitro knockdown of the epigenetic regulator
DNA methyltransferase-1 in GG primary erythroid cells increases the proportion of eGFP(+) cells in culture from 41.9 to 74.1%. Furthermore, eGFP fluorescence is induced >3-fold
after treatment of erythroid precursors with epigenetic drugs known to induce γ-
globin expression, demonstrating the suitability of the Gγ-
globin eGFP reporter for evaluation of γ-
globin inducers. The GG mouse model is therefore a valuable model system for genetic and pharmacologic studies of the regulation of the β-
globin locus and for discovery of novel
therapies for the β-
hemoglobinopathies.