Publication: An in vivo model for analysis of developmental erythropoiesis and globin gene regulation
Issued Date
2014-01-01
Resource Type
ISSN
15306860
08926638
08926638
Other identifier(s)
2-s2.0-84901013745
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Mahidol University
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SCOPUS
Bibliographic Citation
FASEB Journal. Vol.28, No.5 (2014), 2306-2317
Suggested Citation
Bradley McColl, Betty R. Kao, Preeyachan Lourthai, Kasey Chan, Hady Wardan, Mark Roosjen, Orane Delagneau, Linden J. Gearing, Marnie E. Blewitt, Saovaros Svasti, Suthat Fucharoen, Jim Vadolas An in vivo model for analysis of developmental erythropoiesis and globin gene regulation. FASEB Journal. Vol.28, No.5 (2014), 2306-2317. doi:10.1096/fj.13-246637 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/33411
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Title
An in vivo model for analysis of developmental erythropoiesis and globin gene regulation
Abstract
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. © FASEB.