Abstract
Objective: Targeted regulation of β-like globin genes was studied using designer zinc finger transcription factors containing the DNA binding domain of the red cell specific transcription factor erythroid Kruppel-like factor (EKLF) fused to repression domains. Methods: Globin gene expression was analyzed after introduction of the modified transcription factors into cell lines, embryonic stem cells and transgenic mice. Results: As would be predicted, when introduced transiently into cells these transcription factors were effective in repressing the adult β-globin promoter CACCC element, which is the natural target for EKLF. In murine erythroleukemia cells repression of the adult β-globin gene was accompanied by a reactivation of the endogenous embryonic βH1-globin gene. Studies in differentiated embryonic stem cells and transgenic mice confirmed the reactivation of embryonic gene expression during development. Conclusion: Our studies support a competition model for β-globin gene expression and underscore the importance of EKLF in the embryonic/fetal-to-adult globin switch. They also demonstrate the feasibility of designer zinc finger transcription factors in the study of transcriptional control mechanisms at the β-globin locus and as potential gene therapy agents for sickle cell disease and related hemoglobinopathies.
Original language | English (US) |
---|---|
Pages (from-to) | 39-47 |
Number of pages | 9 |
Journal | Experimental Hematology |
Volume | 35 |
Issue number | 1 |
DOIs | |
State | Published - Jan 2007 |
Externally published | Yes |
ASJC Scopus subject areas
- Molecular Biology
- Hematology
- Genetics
- Cell Biology
- Cancer Research