CLOCK
MIM.601851
Circadian rhythmicity of biologic processes is a fundamental property of all eukaryotic and some prokaryotic organisms.
These rhythms are driven by an internal time-keeping system. Changes in the external environment, particularly in the light-dark cycle, entrain this biologic clock.
Under constant environmental conditions devoid of time cues, rhythms driven by the biologic clock show a period near, but usually not equal to, 24 hours.
The bilaterally paired suprachiasmatic nuclei (SCN) of the hypothalamus are thought to contain the master circadian clock that regulates most, if not all, circadian rhythms in mammals.
The CLOCK gene encodes a basic helix-loop-helix (bHLH)-PAS (see 603349) transcription factor that is essential for circadian rhythm.
Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression.
Circadian regulation of the mouse albumin D element-binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions.
Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra- and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density.
In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1alpha and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.
References
Ripperger JA, Schibler U. Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet. 2006 Feb 12; PMID: #16474407#