An in vivo model for analysis of developmental erythropoiesis and globin gene regulation.
- Author(s)
- McColl, B; Kao, BR; Lourthai, P; Chan, K; Wardan, H; Roosjen, M; Delagneau, O; Gearing, LJ; Blewitt, ME; Svasti, S; Fucharoen, S; Vadolas, J;
- Details
- Publication Year 2014-01-17,Volume 28,Issue #5,Page 2306-7
- Journal Title
- FASEB Journal
- Publication Type
- JOURNAL ARTICLE
- 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.-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.
- Publisher
- FASEB
- Keywords
- BAC transgenics, chromatin modification, epigenetics, hemoglobin switching
- Research Division(s)
- Molecular Medicine
- Publisher's Version
- https://doi.org/10.1096/fj.13-246637
- Terms of Use/Rights Notice
- Copyright © 2014 by the Federation of American Societies for Experimental Biology
Creation Date: 2014-02-19 11:35:36