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. Author manuscript; available in PMC: 2013 Sep 3.
Published in final edited form as: Cell. 2008 Sep 5;134(5):728–742. doi: 10.1016/j.cell.2008.08.022

Figure 2. Building blocks of the molecular clock.

Figure 2

The discovery of the core components of the circadian clock was first revealed through forward genetics showing that the clock is encoded by a transcription-translation feedback loop that oscillates with a periodicity of 24 hr in pacemaker neurons and peripheral cells. Subsequent analyses have identified robust outputs of the clock on metabolic pathways in liver, fat and muscle, suggesting convergence of circadian and metabolic pathways at the transcriptional level. The core mammalian clock is comprised of the heterodimeric activators CLOCK and BMAL1 that activate transcription of the genes encoding the repressors PERIOD (PER) and CRYPTOCHROME (CRY). An interlocked regulatory loop directs alternating activation and repression of BMAL1 expression by the nuclear receptors RORα and REV-ERBα, respectively, via binding at the ROR enhancer elements (ROREs) in the BMAL1 promoter. Several other metabolically active nuclear receptors have been identified as modulators of BMAL and CLOCK, including PPARγ and PGC1α. DBP, Albumin D-binding protein; TEF, thyrotroph embryonic factor; HLF, hepatocyte leukemia factor; HSF-1, heat shock factor 1.