| First Author | McColl B | Year | 2014 |
| Journal | FASEB J | Volume | 28 |
| Issue | 5 | Pages | 2306-17 |
| PubMed ID | 24443374 | Mgi Jnum | J:212056 |
| Mgi Id | MGI:5577250 | Doi | 10.1096/fj.13-246637 |
| Citation | McColl B, et al. (2014) An in vivo model for analysis of developmental erythropoiesis and globin gene regulation. FASEB J 28(5):2306-17 |
| abstractText | Expression of fetal gamma-globin in adulthood ameliorates symptoms of beta-hemoglobinopathies by compensating for the mutant beta-globin. Reactivation of the silenced gamma-globin gene is therefore of substantial clinical interest. To study the regulation of gamma-globin expression, we created the GG mice, which carry an intact 183-kb human beta-globin locus modified to express enhanced green fluorescent protein (eGFP) from the Ggamma-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 beta-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 gamma-globin expression, demonstrating the suitability of the Ggamma-globin eGFP reporter for evaluation of gamma-globin inducers. The GG mouse model is therefore a valuable model system for genetic and pharmacologic studies of the regulation of the beta-globin locus and for discovery of novel therapies for the beta-hemoglobinopathies. |
