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primary topic: Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression

Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression
type: AcademicArticle
type: Article
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
volume: 8
issue: 14
author list: authors
type: EPrint
type: ArticleEPrint
is part of: repository

American Society of Hematology
type: Organization

Blood Adv.
type: Collection

Ella Bhagyaraj
type: Person
given name: Ella
family name: Bhagyaraj

Saumyata Kumawat
type: Person
given name: Saumyata
family name: Kumawat

Asheesh Kumar Khare
type: Person
given name: Asheesh Kumar
family name: Khare

Vipashu Kaushal
type: Person
given name: Vipashu
family name: Kaushal

Ravikanth Nanduri
type: Person
given name: Ravikanth
family name: Nanduri

Pawan Gupta
type: Person
given name: Pawan
family name: Gupta

Rashmi Arora
type: Person
given name: Rashmi
family name: Arora

Nancy Ahuja
type: Person
given name: Nancy
family name: Ahuja

Shalini Gupta
type: Person
given name: Shalini
family name: Gupta

Mahathi Sharma
type: Person
given name: Mahathi
family name: Sharma

Rashi Kalra
type: Person
given name: Rashi
family name: Kalra

Sumit Kumar
type: Person
given name: Sumit
family name: Kumar

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primary topic: Nuclear receptor Rev-erbα role in fine-tuning erythropoietin gene expression