期刊
EMBO JOURNAL
卷 26, 期 9, 页码 2295-2306出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601676
关键词
beta-globin switching; DRED; repressor; TR2; TR4
资金
- NCI NIH HHS [P30 CA046592, CA46592] Funding Source: Medline
- NHLBI NIH HHS [HL24415, R01 HL024415, HL73465, R01 HL073465] Funding Source: Medline
- NIGMS NIH HHS [T32 GM007315] Funding Source: Medline
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 b-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 e-globin, but in contrast to induction of gamma-globin in definitive erythroid cells. These temporally specific, gene-selective alterations in e- 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 e- and gamma-globin genes during development, and suggest that their differential utilization controls stage-specific repression of the human e- and gamma-globin genes.
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