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Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBβ in Human Osteosarcoma Cell Cultures
- Title
- Functional Characterization of Circadian Nuclear Receptors REV-ERBα and REV-ERBβ in Human Osteosarcoma Cell Cultures
- Authors
- Cho; Hana; Yun; Ahee; Kim; Joohee; Park; Eunjeong; Jung; Jong-Wha; Chung; Sooyoung; Son; Gi Hoon
- Ewha Authors
- 정수영
- SCOPUS Author ID
- 정수영
- Issue Date
- 2024
- Journal Title
- International Journal of Molecular Sciences
- ISSN
- 1661-6596
- Citation
- International Journal of Molecular Sciences vol. 25, no. 2
- Keywords
- circadian clock; circadian rhythm; REV-ERBs; transcriptome; U2OS cell
- Publisher
- Multidisciplinary Digital Publishing Institute (MDPI)
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- Abstract
- 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. © 2024 by the authors.
- DOI
- 10.3390/ijms25020770
- Appears in Collections:
- ETC > ETC
- Files in This Item:
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ijms-25-00770-v2.pdf(2.5 MB)
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