Embryonic and fetal beta-globin gene repression by the orphan nuclear receptors, TR2 and TR4.
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.
Tanabe
Osamu
O
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109-2200, USA.
McPhee
David
D
Kobayashi
Shoko
S
Shen
Yannan
Y
Brandt
William
W
Jiang
Xia
X
Campbell
Andrew D
AD
Chen
Yei-Tsung
YT
Chang
Chawn shang
Cs
Yamamoto
Masayuki
M
Tanimoto
Keiji
K
Engel
James Douglas
JD
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004622:Embryo, Mammalian / Q000378:metabolism*; D041905:Erythroid Cells / Q000378:metabolism; D005333:Fetus / Q000378:metabolism*; D020868:Gene Silencing; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011401:Promoter Regions, Genetic; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000502:physiology*
C539822:NR2C1 protein, human; C539823:Nr2c1 protein, mouse; C490514:Nr2c2 protein, mouse; D057107:Nuclear Receptor Subfamily 2, Group C, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D005914:Globins