An embryonic/fetal β-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer
An embryonic/fetal β-type globin gene repressor contains a nuclear receptor TR2/TR4 heterodimer
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DOI：
10.1093/emboj/cdf340
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发表时间：
2002-07-01
期刊：
影响因子：
11.4
通讯作者：
Engel, JD
中科院分区：
文献类型：
--
作者：
Tanabe, O;Katsuoka, F;Engel, JD
我们最近描述了一种红细胞ε-珠蛋白基因阻遏物活性，我们将其命名为DRED（直接重复红细胞定型）。我们发现，DRED结合DR 1位点在人类胚胎（β-）和胎儿（γ-）珠蛋白基因启动子的高亲和力，但成人β-珠蛋白启动子没有DR 1元素。DRED是一个540 kDa的复合物;序列测定表明，它含有核孤儿受体TR 2和TR 4。TR 2和TR 4形成异源二聚体，其结合至DR 1和γ启动子DR 1位点。DR 1位点的一个突变导致人类HPFH（胎儿血红蛋白遗传性持续存在）综合征中γ-珠蛋白转录升高，我们发现这种突变在体外降低了TR 2/TR 4结合。这两种受体mRNA在小鼠和人红细胞生成的所有阶段表达;它们的强制转基因表达降低内源性胚胎ε-珠蛋白转录。这些数据表明，TR 2/TR 4形成了一个更大的DRED复合物的核心，抑制胚胎和胎儿珠蛋白转录在定形红细胞，因此，抑制其活性可能是一个有吸引力的干预点治疗镰状细胞贫血。
We recently described an erythroid epsilon-globin gene repressor activity, which we named DRED (direct repeat erythroid-definitive). We show that DRED binds with high affinity to DR1 sites in the human embryonic (epsilon-) and fetal (gamma-) globin gene promoters, but the adult beta-globin promoter has no DR1 element. DRED is a 540 kDa complex; sequence determination showed that it contains the nuclear orphan receptors TR2 and TR4. TR2 and TR4 form a heterodimer that binds to the epsilon and gamma promoter DR1 sites. One mutation in a DR1 site causes elevated gamma-globin transcription in human HPFH (hereditary persistence of fetal hemoglobin) syndrome, and we show that this mutation reduces TR2/TR4 binding in vitro. The two receptor mRNAs are expressed at all stages of murine and human erythropoiesis; their forced transgenic expression reduces endogenous embryonic epsilony-globin transcription. These data suggest that TR2/TR4 forms the core of a larger DRED complex that represses embryonic and fetal globin transcription in definitive erythroid cells, and therefore that inhibition of its activity might be an attractive intervention point for treating sickle cell anemia.