Forger & Peskin (2003) Mammalian Model

This model consists of five genes, PERIOD and CRYPTOCHROME, which each exists in two forms (PER1, PER2, CRY1, CRY2), and REV-ERB-α. CRY forms a negative feedback loop by inhibiting the transcription of all five genes, after being carried into the nucleus by PER. REV-ERB-α relieves this inhibition by selectively inhibiting CRY1. Except transcription, which is modelled as a probability that a gene is activated, all processes are governed directly by mass action.

The mRNAs are transcribed and move into the cytoplasm to be translated.

The PER1 and PER2 proteins can reversibly bind to a kinase, and undergo phosphorylation. Further phosphorylation may then also occur. Both singly and doubly phosphorylated PER, bound or unbound to the kinase, is able to bind to CRY in a reversible manner.

Singly phosphorylated PER, bound or unbound to the kinase or CRY, is the only protein to be transported into the nucleus. This can also bring kinase and CRY into the nucleus, where further PER:CRY complex can form reversibly, and a second phosphorylation of PER can take place. All forms, except free CRY, can also be exported from the nucleus. Nuclear CRY1 and CRY2, in all their forms, bound or unbound to PER or the PER-kinase complex, are able to inhibit transcription from all five promotors.

REV-ERB-α protein can reversible bind to itself, forming a homodimer. Both monomers and dimers can then reversibly enter the nucleus, where further dimerisation and dissociation can take place. The dimer is able to bind to the CRY1 promotor to inhibit transcription.

All cytoplasmic mRNAs, all REV-ERB-α proteins, and unbound PER and CRY are subject to degradation.

Light input to this model is in the form of an increase in the rate of PER1 and PER2 transcription  in response to illumination.

This model is described in PNAS 100 (25): 14806-14811, 2003.