A Dual Reporter Mouse Model of the Human beta-Globin Locus: Applications and Limitations

The human beta-globin locus contains the beta-like globin genes (i.e. fetal gamma-globin and adult beta-globin), which heterotetramerize with alpha-globin subunits to form fetal or adult hemoglobin. Thalassemia is one of the commonest inherited disorders in the world, which results in quantitative defects of the globins, based on a number of genome variations found in the globin gene clusters. Hereditary persistence of fetal hemoglobin (HPFH) also caused by similar types of genomic alterations can compensate for the loss of adult hemoglobin. Understanding the regulation of the human gamma-globin gene expression is a challenge for the treatment of thalassemia. A mouse model that facilitates high-throughput assays would simplify such studies. We have generated a transgenic dual reporter mouse model by tagging the gamma- and beta-globin genes with GFP and DsRed fluorescent proteins respectively in the endogenous human beta-globin locus. Erythroid cell lines derived from this mouse model were tested for their capacity to reactivate the gamma-globin gene. Here, we discuss the applications and limitations of this fluorescent reporter model to study the genetic basis of red blood cell disorders and the potential use of such model systems in high-throughput screens for hemoglobinopathies therapeutics.