The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription

Osamu Tanabe, Yannan Shen, Qinghui Liu, Andrew D. Campbell, Takashi Kuroha, Masayuki Yamamoto, James Douglas Engel

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)

Abstract

When the orphan nuclear receptors TR2 and TR4, the DNA-binding subunits of the DRED repressor complex, are forcibly expressed in erythroid cells of transgenic mice, embryos exhibit a transient mid-gestational anemia as a consequence of a reduction in the number of primitive erythroid cells. GATA-1 mRNA is specifically diminished in the erythroid cells of these TR2/TR4 transgenic embryos as it is in human CD34+ progenitor cells transfected with forcibly expressed TR2/TR4. In contrast, in loss-of-function studies analyzing either Tr2- or Tr4-germline-null mutant mice or human CD34+ progenitor cells transfected with force-expressed TR2 and TR4 short hairpin RNAs (shRNAs), GATA-1 mRNA is induced. An evolutionarily conserved direct repeat (DR) element, a canonical binding site for nuclear receptors, was identified in the GATA1 hematopoietic enhancer (G1HE), and TR2/TR4 binds to that site in vitro and in vivo. Mutation of that DR element led to elevated Gata1 promoter activity, and reduced promoter responsiveness to cotransfected TR2/TR4. Thus, TR2/TR4 directly represses Gata1/GATA1 transcription in murine and human erythroid progenitor cells through an evolutionarily conserved binding site within a well-characterized, tissue-specific Gata1 enhancer, thereby providing a mechanism by which Gata1 can be directly silenced during terminal erythroid maturation.

Original languageEnglish
Pages (from-to)2832-2844
Number of pages13
JournalGenes and Development
Volume21
Issue number21
DOIs
Publication statusPublished - 2007 Nov 1

Keywords

  • DRED
  • Definitive
  • Erythropoiesis
  • G1HE
  • Primitive

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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