A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.
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.
Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, California 92121, USA.
Trey K
TK
Sato
Satchidananda
S
Panda
Loren J
LJ
Miraglia
Teresa M
TM
Reyes
Radu D
RD
Rudic
Peter
P
McNamara
Kinnery A
KA
Naik
Garret A
GA
FitzGerald
Steve A
SA
Kay
John B
JB
Hogenesch
D056930:ARNTL Transcription Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001683:Biological Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000235:genetics*; D020218:Response Elements / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D015534:Trans-Activators; D014157:Transcription Factors; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C539738:RORA protein, human; C539739:Rora protein, mouse