科研之友
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摘要
Expression of fetal -globin in adulthood ameliorates symptoms of -hemoglobinopathies by compensating for the mutant -globin. Reactivation of the silenced -globin gene is therefore of substantial clinical interest. To study the regulation of -globin expression, we created the GG mice, which carry an intact 183-kb human -globin locus modified to express enhanced green fluorescent protein (eGFP) from the G-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 (%26gt;95%) and maintained at low levels into adulthood, demonstrating appropriate developmental regulation of the human -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 %26gt;3-fold after treatment of erythroid precursors with epigenetic drugs known to induce -globin expression, demonstrating the suitability of the G-globin eGFP reporter for evaluation of -globin inducers. The GG mouse model is therefore a valuable model system for genetic and pharmacologic studies of the regulation of the -globin locus and for discovery of novel therapies for the -hemoglobinopathies.McColl, B., Kao, B. R., Lourthai, P., Chan, K., Wardan, H., Roosjen, M., Delagneau, O., Gearing, L. J., Blewitt, M. E., Svasti, S., Fucharoen, S., Vadolas, J. An in vivo model for analysis of developmental erythropoiesis and globin gene regulation.
- 出版日期2014-5
- 单位河北医科大学
