Embryonic and fetal β-globin gene repression by the orphan nuclear receptors, TR2 and TR4

Osamu Tanabe, David McPhee, Shoko Kobayashi, Yannan Shen, William Brandt, Xia Jiang, Andrew D. Campbell, Yei Tsung Chen, Chawn Shang Chang, Masayuki Yamamoto, Keiji Tanimoto, James Douglas Engel

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)

Abstract

The TR2 and TR4 orphan nuclear receptors comprise the DNA-binding core of direct repeat erythroid definitive, a protein complex that binds to direct repeat elements in the embryonic and fetal β-type globin gene promoters. Silencing of both the embryonic and fetal β-type globin genes is delayed in definitive erythroid cells of Tr2 and Tr4 null mutant mice, whereas in transgenic mice that express dominant-negative TR4 (dnTR4), human embryonic ε-globin is activated in primitive and definitive erythroid cells. In contrast, human fetal γ-globin is activated by dnTR4 only in definitive, but not in primitive, erythroid cells, implicating TR2/TR4 as a stage-selective repressor. Forced expression of wild-type TR2 and TR4 leads to precocious repression of ε-globin, but in contrast to induction of γ-globin in definitive erythroid cells. These temporally specific, gene-selective alterations in ε- and γ-globin gene expression by gain and loss of TR2/TR4 function provide the first genetic evidence for a role for these nuclear receptors in sequential, gene-autonomous silencing of the ε- and γ-globin genes during development, and suggest that their differential utilization controls stage-specific repression of the human ε- and γ-globin genes.

Original languageEnglish
Pages (from-to)2295-2306
Number of pages12
JournalEMBO Journal
Volume26
Issue number9
DOIs
Publication statusPublished - 2007 May 2
Externally publishedYes

Keywords

  • DRED
  • Repressor
  • TR2
  • TR4
  • β-globin switching

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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