Daily rhythms of REV-ERBa and its role as transcriptional repressor of clock genes in fish hepatic oscillator

The REV-ERB & alpha; nuclear receptor is a key component of the molecular machinery of circadian oscillators in mammals. While the rhythmic expression of this receptor has been described in teleosts, several critical aspects of its regulation remain unknown, such as which synchronizers entrain its rhythm, and whether it can modulate the expression of other clock genes. The objective of this study was to gain deeper understanding of the role of REV-ERB & alpha; in the fish circadian system. To this end, we first investigated the cues that entrain the rhythm of rev-erb & alpha; expression in the goldfish (Carassius auratus) liver and hypothalamus. A 12-h shift in feeding time induced a parallel shift in the hepatic rhythm of rev-erb & alpha; expression, confirming that this gene is food-entrainable in the goldfish liver. In contrast, light seems the main driver of rev-erb & alpha; rhythmic expression in the hypothalamus. Next, we examined the effects of REV-ERB & alpha; activation on locomotor activity and hepatic expression of clock genes. Subchronic treatment with the REV-ERB & alpha; agonist SR9009 slightly decreased locomotor activity anticipating light onset and food arrival, and downregulated hepatic bmal1a, clock1a, cry1a, per1a and ppar & alpha; expression. This generalized repressing action of REV-ERB & alpha; on the expression of hepatic clock genes was confirmed in vitro by using agonists (SR9009 and GSK4112) and antagonist (SR8278) of this receptor. Overall, the present work re-veals that REV-ERB & alpha; modulates the daily expression of the main genes of the teleostean liver clock, reinforcing its role in the liver temporal homeostasis, which seems highly conserved in both fish and mammals.

Automated summary

This study investigated the role of REV-ERBα in the fish circadian system and found that feeding time and light were important factors regulating its rhythmic expression. The activation of REV-ERBα also affected locomotor activity and the expression of hepatic clock genes. Overall, this study reveals the importance of REV-ERBα in the regulation of the fish circadian clock.