Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBβ in Human Osteosarcoma Cell Cultures

Hana Cho, Ahee Yun, Joohee Kim, Eunjeong Park, Jong Wha Jung, Sooyoung Chung, Gi Hoon Son

Research output: Contribution to journalArticlepeer-review


REV-ERBα and its paralog, REV-ERBβ, encoded by NR1D1 and NR1D2 genes, are key nuclear receptors that link the circadian timing system and metabolic homeostasis. Since heme is an endogenous ligand, REV-ERBs have been considered key components of the circadian molecular clock and can be pharmacologically targeted to treat various circadian rhythm-related diseases, such as cardiometabolic, inflammatory, and neuropsychiatric diseases, as well as cancer. REV-ERBs are believed to be functionally redundant and compensatory, although they often affect the expression of gene subsets in an isoform-specific manner. Therefore, this study aimed to identify the redundant and distinct roles of each isoform in controlling its target genes by comparing the transcriptome profiles of a panel of mutant U2OS human osteosarcoma cells in which either NR1D1 or NR1D2 was ablated. Indeed, our transcriptomic analyses revealed that most REV-ERB-regulated genes are controlled by redundant or even additive actions. However, the RNA expression profiles of each single mutant cell line also provide strong evidence for isoform-dependent actions. For example, REV-ERBα is more responsible for regulating the NF-κΒ signaling pathway, whereas a group of extracellular matrix components requires REV-ERBβ to maintain their expression. We found that REV-ERBs have isoform-selective functions in the regulation of certain circadian output pathways despite their overlapping roles in the circadian molecular clock. Thus, the development of isoform-selective REV-ERB modulators can help treat metabolic disturbances and certain types of cancer.

Original languageEnglish
Article number770
JournalInternational Journal of Molecular Sciences
Issue number2
StatePublished - Jan 2024

Bibliographical note

Publisher Copyright:
© 2024 by the authors.


  • REV-ERBs
  • U2OS cell
  • circadian clock
  • circadian rhythm
  • transcriptome


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