REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output
REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output
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DOI：
10.1038/s41598-019-46656-0
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发表时间：
2019-07-15
影响因子：
4.6
通讯作者：
Yagita, Kazuhiro
中科院分区：
文献类型：
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作者：
Ikeda, Ryosuke;Tsuchiya, Yoshiki;Yagita, Kazuhiro
生物钟以24小时为周期调节行为和生理过程。核受体REV-ERB α和REV-ERB β作为转录抑制因子参与细胞自主昼夜节律转录/翻译反馈回路。许多研究也证明REV-ERBs在代谢、神经元和炎症功能的调节中起关键作用，包括胆汁酸代谢、脂质代谢和炎症细胞因子的产生。鉴于rev - erbb具有多种功能，阐明rev - erbb发挥其功能的机制具有重要意义。为此，我们建立了Rev-erb α /Rev-erb β双敲除小鼠胚胎干（ES）细胞模型，分析了生物钟和生物钟控制输出基因的表达。一项全面的mRNA-seq分析显示，双敲除Rev-erb α和Rev-erb β并不会取消e -box调节的核心时钟基因的表达节奏，但会极大地改变其他多种节律表达的输出基因。值得注意的是，REV-ERB α / β缺乏并不影响PER2的昼夜表达节律，而REV-ERB靶基因Bmal1和Npas2则显著上调。这项研究强调了REV-ERBs作为哺乳动物生物钟关键输出介质的相关性。
The circadian clock regulates behavioural and physiological processes in a 24-h cycle. The nuclear receptors REV-ERB alpha and REV-ERB beta are involved in the cell-autonomous circadian transcriptional/translational feedback loops as transcriptional repressors. A number of studies have also demonstrated a pivotal role of REV-ERBs in regulation of metabolic, neuronal, and inflammatory functions including bile acid metabolism, lipid metabolism, and production of inflammatory cytokines. Given the multifunctional role of REV-ERBs, it is important to elucidate the mechanism through which REV-RBs exert their functions. To this end, we established a Rev-erb alpha/Rev-erb beta double-knockout mouse embryonic stem (ES) cell model and analyzed the circadian clock and clock-controlled output gene expressions. A comprehensive mRNA-seq analysis revealed that the double knockout of both Rev-erb alpha and Rev-erb beta 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-ERB alpha/beta 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.