creators_name: Kumar, Sumit
creators_name: Arora, Rashmi
creators_name: Gupta, Shalini
creators_name: Ahuja, Nancy
creators_name: Bhagyaraj, Ella
creators_name: Nanduri, Ravikanth
creators_name: Kalra, Rashi
creators_name: Khare, Asheesh Kumar
creators_name: Kumawat, Saumyata
creators_name: Kaushal, Vipashu
creators_name: Sharma, Mahathi
creators_name: Gupta, Pawan
type: article
datestamp: 2026-02-07 04:39:25
lastmod: 2026-02-07 04:39:25
metadata_visibility: show
title: Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression
abstract: 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-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.
date: 2024-07
publication: Blood Adv.
volume: 8
number: 14
publisher: American Society of Hematology
pagerange: 3705-3717
citation:   Kumar, Sumit and Arora, Rashmi and Gupta, Shalini and Ahuja, Nancy and Bhagyaraj, Ella and Nanduri, Ravikanth and Kalra, Rashi and Khare, Asheesh Kumar and Kumawat, Saumyata and Kaushal, Vipashu and Sharma, Mahathi and Gupta, Pawan  (2024) Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression.  Blood Adv., 8 (14).  pp. 3705-3717.