Altered regulation of β-like globin genes by a redesigned erythroid transcription factor

Deepa Manwani, Mariann Galdass, James J. Bieker

Research output: Contribution to journalArticle

10 Scopus citations

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 languageEnglish (US)
Pages (from-to)39-47
Number of pages9
JournalExperimental Hematology
Volume35
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Hematology
  • Genetics
  • Cell Biology
  • Cancer Research

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