Adult stage γ-globin silencing is mediated by a promoter direct repeat element

Akane Omori, Osamu Tanabe, James Douglas Engel, Akiyoshi Fukamizu, Keiji Tanimoto

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

Abstract

The human β-like globin genes (5′-ε-Gγ-Aγ- δ-β-3′) are temporally expressed in sequential order from the 5′ to 3′ end of the locus, but the nonadult ε- and γ-globin genes are autonomously silenced in adult erythroid cells. Two cis elements have been proposed to regulate definitive erythroid γ-globin repression: the DR (direct repeat) and CCTTG elements. Since these two elements partially overlap, and since a well-characterized HPFH point mutation maps to an overlapping nucleotide, it is not clear if both or only one of the two participate in γ-globin silencing. To evaluate the contribution of these hypothetical silencers to γ-globin regulation, we generated point mutations that individually disrupted either the single DR or all four CCTTG elements. These two were separately incorporated into human β-globin yeast artificial chromosomes, which were then used to generate γ-globin mutant transgenic mice. While DR element mutation led to a dramatic increase in Aγ-globin expression only during definitive erythropoiesis, the CCTTG mutation did not affect adult stage transcription. These results demonstrate that the DR sequence element autonomously mediates definitive stage-specific γ-globin gene silencing.

Original languageEnglish
Pages (from-to)3443-3451
Number of pages9
JournalMolecular and cellular biology
Volume25
Issue number9
DOIs
Publication statusPublished - 2005 May

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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