A functional genomics strategy reveals Rora as a component of the mammalian circadian clock

Neuron. 2004 Aug 19;43(4):527-37. doi: 10.1016/j.neuron.2004.07.018.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ARNTL Transcription Factors
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors
  • Biological Clocks / genetics*
  • Circadian Rhythm / genetics*
  • Genomics / methods*
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Neurologic Mutants
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Promoter Regions, Genetic
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid / biosynthesis
  • Receptors, Retinoic Acid / genetics*
  • Response Elements / genetics
  • Trans-Activators
  • Transcription Factors / genetics
  • Transcription Factors / metabolism

Substances

  • ARNTL Transcription Factors
  • ARNTL protein, human
  • Arntl protein, mouse
  • Basic Helix-Loop-Helix Transcription Factors
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • RNA, Messenger
  • RORA protein, human
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Rora protein, mouse
  • Trans-Activators
  • Transcription Factors