PDF(Pubmed)
Abstract：
UNASSIGNED: The regulation of red blood cell (RBC) homeostasis by erythropoietin (EPO) is critical for O2 transport and maintaining the adequate number of RBCs in vertebrates. Therefore, dysregulation in EPO synthesis results in disease conditions such as polycythemia in the case of excessive EPO production and anemia, which occurs when EPO is inadequately produced. EPO plays a crucial role in treating anemic patients; however, its overproduction can increase blood viscosity, potentially leading to fatal heart failure. Consequently, the identification of druggable transcription factors and their associated ligands capable of regulating EPO offers a promising therapeutic approach to address EPO-related disorders. This study unveils a novel regulatory mechanism involving 2 pivotal nuclear receptors (NRs), Rev-ERBA (Rev-erbα, is a truncation of reverse c-erbAa) and RAR-related orphan receptor A (RORα), in the control of EPO gene expression. Rev-erbα acts as a cell-intrinsic negative regulator, playing a vital role in maintaining erythropoiesis at the correct level. It accomplishes this by directly binding to newly identified response elements within the human and mouse EPO gene promoter, thereby repressing EPO production. These findings are further supported by the discovery that a Rev-erbα agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, RORα functions as a positive regulator of EPO gene expression, also binding to the same response elements in the promoter to induce EPO production. Finally, the results of this study revealed that the 2 NRs, Rev-erbα and RORα, influence EPO synthesis in a negative and positive manner, respectively, suggesting that the modulating activity of these 2 NRs could provide a method to target disorders linked with EPO dysregulation.
摘要：
促红细胞生成素（EPO）对RBC稳态的调节对于O2运输和维持脊椎动物中足够数量的RBC至关重要。因此,在EPO产生过多和贫血的情况下，EPO合成失调会导致红细胞增多症等疾病，这发生在EPO生产不足时。EPO在治疗贫血患者中起着至关重要的作用；然而，它的过量生产会增加血液粘度，可能导致致命的心力衰竭.因此,能够调节EPO的可药用转录因子(TFs)及其相关配体的鉴定为解决EPO相关疾病提供了有希望的治疗方法.这项研究揭示了一种涉及两个关键核受体（NRs）的新调控机制。Rev-erbα和RORα，在EPO基因表达的控制中。Rev-erbα充当细胞固有的负调节剂，在将红细胞生成维持在正确水平中起着至关重要的作用。它通过直接结合到人和小鼠EPO基因启动子内新鉴定的反应元件来实现这一目标，从而抑制了EPO的生产。这些发现进一步得到Rev-erbα激动剂(SR9011)有效抑制小鼠中缺氧诱导的EPO表达的发现的支持。相比之下,RORα作为EPO基因表达的正调节因子,也与启动子中相同的反应元件结合以诱导EPO产生。最后,这项研究的结果表明，这两个NR，Rev-erbα,和RORα,以消极和积极的方式影响EPO合成，这表明这两种NRs的调节活性可以提供一种靶向与EPO失调相关的疾病的方法。
