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The TR2 and TR4 orphan nuclear receptors repress Gata1 transcription

¹ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA; ² Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, and JST-ERATO Environmental Response Project, Sendai 980-8575, Japan

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.

[Keywords: Primitive; definitive; erythropoiesis; DRED; G1HE]]

Received January 5, 2007; revised version accepted September 12, 2007.

E-MAIL engel{at}umich.edu; FAX (734) 763-1166.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1593307

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