TY  - JOUR
ID  - open3323
UR  - http://crdd.osdd.net/open/3323/
IS  - 14
A1  - Kumar, Sumit
A1  - Arora, Rashmi
A1  - Gupta, Shalini
A1  - Ahuja, Nancy
A1  - Bhagyaraj, Ella
A1  - Nanduri, Ravikanth
A1  - Kalra, Rashi
A1  - Khare, Asheesh Kumar
A1  - Kumawat, Saumyata
A1  - Kaushal, Vipashu
A1  - Sharma, Mahathi
A1  - Gupta, Pawan
Y1  - 2024/07//
N2  - ABSTRACT: 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-erb?, is a truncation of reverse c-erbAa) and RAR-related orphan receptor A (ROR?), in the control of EPO gene expression. Rev-erb? 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-erb? agonist (SR9011) effectively suppresses hypoxia-induced EPO expression in mice. In contrast, ROR? 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-erb? and ROR?, 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.
PB  - American Society of Hematology
JF  - Blood Adv.
VL  - 8
TI  - Nuclear receptor Rev-erb? role in fine-tuning erythropoietin gene expression
SP  - 3705
EP  - 3717
ER  -