ARNTL

ARNTL, also known as BMAL1 (brain and muscle ARNT-like 1), is a core transcription factor of the mammalian circadian clock. The gene encodes a basic helix-loop-helix-PAS domain protein that forms heterodimers with CLOCK or NPAS2 to regulate daily gene expression. The CLOCK:BMAL1 complex binds to E-box elements (CACGTG) in the promoters of clock-controlled genes, driving their transcription in a roughly 24-hour cycle. This set includes the Period (PER1, PER2) and Cryptochrome (CRY1, CRY2) genes, as well as additional regulators such as REV-ERBα and DBP, establishing a transcription-translation feedback loop that coordinates circadian rhythms in physiology and behavior.

ARNTL activity is modulated at multiple levels. The protein participates in a feedback system with PER and CRY proteins, which inhibit CLOCK:BMAL1 activity to generate oscillations. Post-translational modifications, including phosphorylation by CK1δ/ε and acetylation regulated by SIRT1, influence BMAL1 stability and transcriptional activity. CLOCK:BMAL1 activity is also entrained by external cues such as light, feeding, and temperature, enabling synchrony between the central clock in the suprachiasmatic nucleus and peripheral clocks in tissues like liver, adipose tissue, and muscle.

Biological significance and clinical relevance include regulation of sleep–wake cycles, metabolism, hormone secretion, and energy balance. In animal models, loss of BMAL1 disrupts circadian rhythms and leads to metabolic disturbances and altered aging phenotypes. In humans, common variants in ARNTL have been linked in population studies with diurnal preference and metabolic traits, reflecting its broad role in physiology and disease risk.