A Functional Genomics Strategy Reveals Rora as a Component of the Mammalian Circadian Clock

Abstract

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.

Circadian clocks: from stem cells to tissue homeostasis and regeneration

“…A second feedback loop consists of two sets of nuclear receptors: the transcriptional activator ROR (RAR‐related orphan receptor, RORα/β) and transcriptional repressor REV‐ERB (REV‐ERBα/β, encoded by Nr1d1/2 ) that are all activated by the BMAL1:CLOCK heterodimer 18, 19. RORs and REV‐ERBs compete for Rev‐ErbA/ROR response elements (RRE) within the regulatory sequence of core clock genes such as Bmal1 , Cry1 , E4bp4, and Npas2 to fine‐tune their transcription 20, 21.…”

Circadian regulation of lipid metabolism

“…This is achieved in part by REV-ERBα-dependent recruitment of the nuclear receptor corepressor/histone deacetylase 3 complex. Additionally, ROR genes (RORα, RORβ and RORγ) are rhythmically expressed and their protein products activate Bmal1 and Npas2 transcription by binding to ROR response elements, thus competing with and having the opposite effect of REV-ERB proteins (43)(44)(45) . REV-ERBα might also act as a transcriptional repressor for Clock by binding to a REV-ERB response element, although ROR proteins do not appear to regulate Clock gene expression (46) .…”

Circadian genes, rhythms and the biology of mood disorders

“…Upon entering the nucleus, they can repress the actions of CLOCK/BMAL1, thus creating a negative feedback loop. In addition, there is an adjoining loop in which CLOCK/BMAL1 activates the transcription of Rev-erbα and Rorα (Sato et al, 2004;Guillaumond et al, 2005). Once translated, these proteins can bind to the promoter of the BMAL1 gene and both positively and negatively affect its transcription.…”