The human ζ-globin gene (HBZ) is transcribed in primitive erythroid cells only during the embryonic stages of development. Reactivation of this embryonic globin synthesis would likely alleviate symptoms both in α-thalassemia and sickle-cell disease. However, the molecular mechanisms controlling ζ-globin expression have remained largely undefined. Moreover, the pharmacologic agent capable of inducing ζ-globin production is currently unavailable. Here, we show that TRIAC, a bioactive thyroid hormone metabolite, significantly induced ζ-globin gene expression during zebrafish embryogenesis. The induction of ζ-globin expression by TRIAC was also observed in human K562 erythroleukemia cell line and primary erythroid cells. Thyroid hormone receptor α (THRA) deficiency abolished the ζ-globin-inducing effect of TRIAC. Furthermore, THRA could directly bind to the distal enhancer regulatory element to regulate ζ-globin expression. Our study provides the first evidence that TRIAC acts as a potent inducer of ζ-globin expression, which might serve as a new potential therapeutic option for patients with severe α-thalassemia or sickle-cell disease.

中文翻译：

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3,3',5-三碘甲状腺乙酸 (TRIAC) 通过甲状腺激素受体 α 诱导胚胎 ζ-珠蛋白表达

人类 ζ-珠蛋白基因 (HBZ) 仅在胚胎发育阶段在原始红细胞中转录。这种胚胎珠蛋白合成的重新激活可能会减轻α-地中海贫血和镰状细胞病的症状。然而，控制 ζ-珠蛋白表达的分子机制在很大程度上仍未确定。此外，目前还没有能够诱导 ζ-珠蛋白产生的药物。在这里，我们展示了 TRIAC，一种生物活性甲状腺激素代谢物，在斑马鱼胚胎发生过程中显着诱导了 ζ-珠蛋白基因表达。在人 K562 红白血病细胞系和原代红细胞中也观察到 TRIAC 对 ζ-珠蛋白表达的诱导。甲状腺激素受体α (THRA) 缺乏消除了 TRIAC 的 ζ-珠蛋白诱导作用。此外，THRA 可以直接结合远端增强子调控元件来调控 ζ-珠蛋白的表达。我们的研究提供了第一个证据，证明 TRIAC 可作为 ζ-珠蛋白表达的有效诱导剂，这可能成为严重 α-地中海贫血或镰状细胞病患者的新潜在治疗选择。