Function of REV-ERBa/b in regulation of cellular circadian physiology

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06338
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 44050:Animal physiological chemistry, physiology and behavioral biology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Tsuchiya Yoshiki 京都府立医科大学, 医学(系)研究科(研究院), 講師 (30456777)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 概日リズム / 核内受容体 / 転写フィードバックループ

Outline of Final Research Achievements

The nuclear receptors REV-ERBα and REV-ERBβ are involved in the cell-autonomous circadian transcriptional/ translational feedback loops as well as in regulation of metabolic, neuronal, and inflammatory functions. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-ERBs exert their functions. To this end, we established a Rev-erbα/Rev-erbβ double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout does not abrogate expression rhythms of E-box-regulated core clock genes but drastically changes a diverse set of other rhythmically-expressed output genes. Of note, REV-ERBα/β deficiency does not compromise circadian expression rhythms of PER2, while REV-ERB target genes, Bmal1 and Npas2, are significantly upregulated. This study highlight the relevance of REV-ERBs as pivotal output mediators of the mammalian circadian clock.

Free Research Field

概日リズム

Academic Significance and Societal Importance of the Research Achievements

本研究では、代謝や免疫、神経機能などの広範な生理機能を担う遺伝子群の発現制御に関わるREV-ERBα/βがこれらの生理機能と概日時計を結ぶハブとしての役割を果たしていることを示した。本研究で樹立したREV-ERBα/β欠損ES細胞を神経細胞や筋細胞など特定の細胞種に分化させることで、概日リズム出力機構におけるREV-ERBα/βの役割を細胞レベルで解析することが可能である。REV-ERBの活性調節は概日リズム関連疾患の治療標的としても有望であると考えられ、本研究の発展はREV-ERBが関与する生理機能リズム制御機構の解明および代謝や免疫など様々な生理機能疾患の治療応用に繋がると期待される。