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).