3,3′,5-Triiodothyroacetic acid (TRIAC) induces embryonic ζ-globin expression via thyroid hormone receptor α

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

Automated summary

The study identified TRIAC, a bioactive thyroid hormone metabolite, as a potent inducer of zeta-globin expression, which could potentially be a new therapeutic option for patients with severe alpha-thalassemia or sickle-cell disease. The researchers also found that THRA deficiency abolished the zeta-globin-inducing effect of TRIAC, suggesting a direct regulatory role of THRA in zeta-globin expression.