REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output

Ikeda, Ryosuke; Tsuchiya, Yoshiki; Koike, Nobuya; Umemura, Yasuhiro; Inokawa, Hitoshi; Ono, Ryutaro; Inoue, Maho; Sasawaki, Yuh; Grieten, Tess; Okubo, Naoki; Ikoma, Kazuya; Fujiwara, Hiroyoshi; Kubo, Toshikazu; Yagita, Kazuhiro

doi:10.1038/s41598-019-46656-0

Cited by 76 publications

(58 citation statements)

References 41 publications

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“…Moreover, several studies demonstrate that circadian disruption induces leptin resistance, even without changes in feeding rhythms 41,[43][44][45] , suggesting that leptin signaling is highly dynamic in response to both external feeding cues and internal circadian timing to maintain long-term energy balance. Indeed, central leptin signaling has been demonstrated to be diurnal using a Bmal1 DKO model that completely impaired cell-autonomous clocks 42 , which does not occur following REV-ERBs deletion 14,46,47 . As REV-ERB expression is Bmal1-dependent 48 , the present work suggests a direct role for REV-ERBs in the effect of BMAL1 on leptin signaling.…”

Section: Discussionmentioning

confidence: 99%

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

Adlanmérini¹,

Nguyen²,

Krusen³

et al. 2021

Journal of Clinical Investigation

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Section: Discussionmentioning

confidence: 99%

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

Adlanmérini¹,

Nguyen²,

Krusen³

et al. 2021

Journal of Clinical Investigation

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“…HDAC3 is required for the inhibition of Rev-erbα activity. Rev-erbα directly binds to the BMAL1 gene promoter through two RORE (retinoid-related orphan receptors) binding sites and inhibits its activity [34]. What's more, BMAL1 is an important regulation mechanisms in circadian rhythm of human energy metabolism.…”

Section: Discussionmentioning

confidence: 99%

Roles of HDAC3-Orchestrated Circadian Clock Gene Oscillations in Diabetic Rats Following Myocardial Ischemia / Reperfusion Injury

et al. 2020

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Background: Circadian clock has been closely related to the development of diabetes mellitus and cardiovascular disease; the disruption of circadian clock exacerbates myocardial ischemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop by recruitmenting the expression pattern of circadian nuclear receptor Rev-erbα, then to maintain the stability of circadian gene such as BMAL1. In this research, we explored the mechanism of HDAC3-orchestrated Rev-erbα/BMAL1 pathway in increasing MI/RI vulnerability of diabetes, and its relationship with mitophagy. Methods and results: Streptozocin (STZ) was used to establish type 1 diabetes by intraperitoneal injection. After 8 weeks, the diabetic and non-diabetic rats were exposed to MI/RI by ligating the left anterior descending coronary artery (LDA) for 30 minutes and reperfusion for 120 minutes at four time points of zeitgeber (ZT) 0, 6, 12 and 18. Circadian clock gene oscillations were rapidly attenuated in diabetic I/RI hearts, versus sham and/or the non-diabetic I/RI hearts, in accord with circadian mitophagy. By utilizing AAV-HDAC3 to knockdown HDAC3 expression, HDAC3 deficiency significantly attenuated diabetic MI/RI associated with increased autophagy activation. In vitro experiments, primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA exposed to hypoxia/reoxygenation (H/R). The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high glucose condition with decreased BMAL1 expression and autophagy level. After H/R stimulation, the cell injury was obviously increased with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 level. Moreover, high glucose aggravated H/R injury compared with low glucose by reducing autophagy level, increasing the levels of HDAC3 and Rev-erbα and down-regulating BMAL1 expression. HDAC3 and Rev-erbα siRNA can alleviate high glucose and H/R-induced injury by up-regulating BMAL1 expression and mitophagy levels. Conclusion: These findings suggest that in diabetic rat MI/RI , the circadian clocks were rapidly impaired then to inhibit mitophagy; cardiac-targeted manipulation of HDAC3-orchestrated Rev-erbα/BMAL1 pathway may be the mechanism of the decreased toleration to ischemia with a circadian dependent variability.

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“…5A). Furthermore, the expression of Hes7 exhibited the oscillation with a circadian period in 28-day differentiated Per2 Luc ESCs (29) and human epidermal stem cells (30) (Fig. 5B, C Because the loss of the Hes7 ultradian expression rhythm and the genetic ablation or overexpression of Lfng in the mouse cause segmentation defects (22,32,33), oscillatory expressions of Hes7 and Lfng genes with adequate ultradian rhythm are essential for mammalian development.…”

Section: Oscillation Of the Segmentation Clock Was Observed Even Durimentioning

confidence: 97%

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

Umemura

Koike

Tsuchiya

et al. 2020

Preprint

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In the mammalian developmental process, the segmentation clock and circadian clock appear sequentially in the embryo. However, there is no clear information about the biological significance of the mutual exclusiveness of these rhythms. Here we show that excess of the circadian components CLOCK/BMAL1 in mouse embryonic organoids, induced presomitic mesoderm and gastruloids, disrupts the Hes7 ultradian rhythm and somitogenesis. RNA sequencing analysis showed that CLOCK/BMAL1 activates the signaling pathways regulating Hes7. After establishment of the circadian clock, the expression of endogenous Hes7 and another segmentation clock gene, Lfng, tended to fluctuate with a circadian period, implying that the circadian clock potentially interferes with the segmentation clock. These results suggest that strict timing regulation of the emergence of circadian clock oscillation is essential for mammalian development.

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REV-ERBα and REV-ERBβ function as key factors regulating Mammalian Circadian Output

Cited by 76 publications

References 41 publications

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice

Roles of HDAC3-Orchestrated Circadian Clock Gene Oscillations in Diabetic Rats Following Myocardial Ischemia / Reperfusion Injury

Circadian key component CLOCK/BMAL1 interferes with segmentation clock in mouse embryonic organoids

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