CLOCKBMAL1

CLOCKBMAL1 refers to the CLOCK-BMAL1 transcription factor complex, the principal activator of circadian gene expression in mammals. CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (also known as ARNTL, Mop3 in some species) form a heterodimer that binds to E-box elements in the promoters of clock-controlled genes, including Period (PER1-3) and Cryptochrome (CRY1-2). Through this action, CLOCK-BMAL1 drives rhythmic transcription and establishes the core circadian transcription-translation feedback loop.

Structure and mechanism: CLOCK and BMAL1 are basic helix-loop-helix PAS domain transcription factors. Dimerization via their PAS domains enables specific DNA binding to E-box sequences and activation of target gene transcription. The complex can recruit coactivators and influence chromatin state at clock gene promoters; CLOCK also contributes transcriptional activation and may participate in chromatin remodeling processes that facilitate rhythmic gene expression.

Regulation and clockwork: The circadian rhythm arises when PER and CRY proteins accumulate, form complexes, and translocate to the nucleus to inhibit CLOCK-BMAL1 activity, thereby reducing their own transcription. The cycle resets as PER/CRY are degraded. Post-translational modifications, notably phosphorylation by kinases such as CK1δ/ε and GSK3β, regulate the stability and activity of clock proteins and thus period length. Environmental cues like light entrain the clock by modulating CLOCK-BMAL1 activity in central and peripheral tissues.

Physiological relevance: CLOCK-BMAL1 coordinates rhythms in metabolism, sleep-wake cycles, hormone secretion, and liver and adipose tissue function. Genetic disruption of CLOCK or BMAL1 disrupts circadian behavior and metabolic regulation in model organisms, with implications for sleep disorders, obesity, and related diseases, reflecting the clock’s broad physiological influence.