Integration of the nuclear receptor REV-ERBα linked with circadian oscillators in the expressions ofAlas1, Ppargc1a, andIl6genes in rat granulosa cells

Jun 24, 2015Chronobiology international

REV-ERBα's role with daily rhythms in controlling key gene activity in rat ovarian support cells

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Abstract

REV-ERBα may repress the expressions of Alas1, Ppargc1a, and Il6 in granulosa cells.

Circadian oscillations of the Per2 promoter were observed in matured granulosa cells after treatment with REV-ERBα agonists and antagonists.
GSK4112 treatment lengthened the period and shortened the amplitude of circadian oscillations, while SR8278 had a subtle effect on daily expression profiles.
The natural ligand heme elongated circadian oscillation periods and reduced their amplitudes in granulosa cells stimulated with luteinizing hormone.
Heme treatment repressed the expressions of clock genes and the selected target genes, while Rev-erbα knockdown increased their transcript levels.
These findings indicate a functional role for REV-ERBα in regulating circadian rhythms and gene expression in ovarian cells.

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The nuclear receptor REV-ERBα links circadian rhythms and numerous physiological processes, but its physiological role in ovaries remains largely unknown. The aim of this study was to determine the potential role of REV-ERBα in the regulation of the transcription of its putative target genes in granulosa cells (GCs) prepared from Per2-destablized luciferase (dLuc) reporter gene transgenic rats. Alas1, Ppargc1a, and Il6 were chosen as representatives for genes analysis. A real-time monitoring system of Per2 promoter activity was performed to detect Per2-dLuc circadian oscillations. Two agonists (GSK4112, heme) and an antagonist (SR8278) of REV-ERBα as well as Rev-erbα siRNA knockdown were used to identify its target genes. Clear Per2-dLuc circadian oscillations were generated in matured GCs after synchronization with GSK4112 or SR8278. GSK4112 treatment lengthened and SR8278 treatment shortened the period of circadian oscillations in matured GCs stimulated with or without luteinizing hormone (LH). GSK4112 showed an inhibitory effect on the amplitude of circadian oscillations and caused an arrhythmic expression of canonical clock genes. SR8278 also had a subtle effect on their daily expression profiles, but the treatment resulted only in the arrhythmic expression of Rev-erbα. These findings indicate the functional biological activity of REV-ERBα in response to its ligands. Its natural ligand heme further elongated the period of circadian oscillations and alleviated their amplitudes in GCs cultured with LH. Heme treatment also repressed the expressions of clock genes, Alas1, Il6, and Ppargc1a. Rev-erbα knockdown up-regulated these transcript levels. Collectively, these data extend the recent finding to rat GCs and demonstrate that REV-ERBα represses the expressions of Alas1, Ppargc1a, and Il6, providing novel insights into the physiological significance of REV-ERBα in ovarian circadian oscillators.

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Integration of the nuclear receptor REV-ERBα linked with circadian oscillators in the expressions ofAlas1, Ppargc1a, andIl6genes in rat granulosa cells

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