Derepression of human embryonic ζ-globin promoter by a locus-control region sequence

B. L. Huang, I. R. Fan-Chiang, S. C. Wen, H. C. Koo, W. Y. Kao, N. R. Gavva, C. K.James Shen

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

A multiple protein-DNA complex formed at a human α-globin locus- specific regulatory element, HS-40, confers appropriate developmental expression pattern on human embryonic ζ-globin promoter activity in humans and transgenic mice. We show here that introduction of a 1-bp mutation in an NF-E2/AP1 sequence motif converts HS-40 into an erythroid-specific locus- control region. Cis-linkage with this locus-control region, in contrast to the wild-type HS-40, allows erythroid lineage-specific derepression of the silenced human ζ-globin promoter in fetal and adult transgenic mice. Furthermore, ζ-globin promoter activities in adult mice increase in proportion to the number of integrated DNA fragments even at 19 copies/genome. The mutant HS-40 in conjunction with human ζ-globin promoter thus can be used to direct position-independent and copy number-dependent expression of transgenes in adult erythroid cells. The data also supports a model in which competitive DNA binding of different members of the NF-E2/AP1 transcription factor family modulates the developmental stage specificity of an erythroid enhancer. Feasibility to reswitch on embryonic/fetal globin genes through the manipulation of nuclear factor binding at a single regulatory DNA motif is discussed.

Original languageEnglish
Pages (from-to)14669-14674
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number25
DOIs
Publication statusPublished - Dec 8 1998
Externally publishedYes

Keywords

  • Competitive factor binding
  • Enhancer
  • Globin switch
  • Passive repression
  • Transgenic mice

ASJC Scopus subject areas

  • General

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