Figure 1.

The network of the mammalian molecular oscillator. The core loop (red shaded circle), responsible for generating rhythms of about 24 h, is composed of activation of the Per genes by BMAL1 (red) and CLOCK (blue) and the increasing repression of Per gene expression by the accumulation of its own gene product. The feedback inhibition by the PER proteins is delayed by posttranslational modifications and interaction with the CRY proteins (not shown). In the stabilizing loop (blue circle), the Rev-Erbα gene (Reverse-erb alpha) is also activated by BMAL1 and CLOCK (not shown) and later on repressed by the PER proteins but immediately REV-ERBα starts to inhibit transcription of the Bmal1 and Clock genes and of its own gene. PER2 can interact with REV-ERBα (or PPARα, not shown) to regulate the Bmal1 gene. The overall organization of the network allows for a tight synchronization of the core and stabilizing loops. Adapted from Ripperger and Albrecht (2012).