Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

Jan 19, 2002Biochemical and biophysical research communications

Feedback loops in the mammalian body clock: BMAL1 controls itself and is influenced by CRY1, CRY2, and PER2 proteins

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Abstract

Transcription of the mouse Bmal1 gene is controlled by interactions between several clock proteins.

High levels of CRY1, CRY2, and PER2 activate mBmal1 transcription.
BMAL1-CLOCK dimers repress mBmal1 transcription.
CRY, PER2, and BMAL1-CLOCK exhibit bidirectional roles in transcription regulation.
The interactions of these proteins may contribute to the stability and timing of circadian rhythms.
A proposed negative feedback loop between BMAL1 and CRY/PER2 could form a positive forward loop, enhancing rhythmic regulation.

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Transcriptional regulation appears to be fundamental to circadian oscillations of clock gene expression. These oscillations are believed to control output rhythms. The transcriptional feedback loop and a model of interlocked loops have been proposed as the basis for these oscillations. We characterized the genomic structure of the mouse Bmal1 gene (mBmal1) and defined the mBmal1 promoter region. Transcription of mBmal1 was activated by CRY1, CRY2, and PER2, and was repressed by BMAL1-CLOCK dimers. Therefore, CRY, PER2, and BMAL1-CLOCK play bidirectional roles in transcription when they are at high levels by late day and midnight, respectively. This underlies the opposite phase of BMAL1 compared to CRY and PER. We propose that a BMAL1 negative feedback loop interlocks with the CRY and PER2 negative feedback loop by inter-activation, forming a third positive forward loop. This transcriptional model suggests a molecular basis for the maintenance of stability, persistence, and period of circadian rhythms. The transcriptional potency of CRY is predominant within the mammalian clock, suggesting a clearance mechanism for CRY in period maintenance. (c)2002 Elsevier Science (USA).

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Interactivating Feedback Loops within the Mammalian Clock: BMAL1 Is Negatively Autoregulated and Upregulated by CRY1, CRY2, and PER2

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