Embryonic and Fetal Beta-Globin Gene Repression by the Orphan Nuclear Receptors, TR2 and TR4

EMBO J. 2007 May 2;26(9):2295-306. doi: 10.1038/sj.emboj.7601676. Epub 2007 Apr 12.

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 beta-type globin gene promoters. Silencing of both the embryonic and fetal beta-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 epsilon-globin is activated in primitive and definitive erythroid cells. In contrast, human fetal gamma-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 epsilon-globin, but in contrast to induction of gamma-globin in definitive erythroid cells. These temporally specific, gene-selective alterations in epsilon- and gamma-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 epsilon- and gamma-globin genes during development, and suggest that their differential utilization controls stage-specific repression of the human epsilon- and gamma-globin genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Embryo, Mammalian / metabolism*
  • Erythroid Cells / metabolism
  • Fetus / metabolism*
  • Gene Silencing*
  • Globins / biosynthesis*
  • Globins / genetics
  • Humans
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Nuclear Receptor Subfamily 2, Group C, Member 1
  • Promoter Regions, Genetic
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*
  • Receptors, Thyroid Hormone / genetics
  • Receptors, Thyroid Hormone / physiology*

Substances

  • NR2C1 protein, human
  • Nr2c1 protein, mouse
  • Nr2c2 protein, mouse
  • Nuclear Receptor Subfamily 2, Group C, Member 1
  • Receptors, Steroid
  • Receptors, Thyroid Hormone
  • Globins