ARNTL

Aryl hydrocarbon receptor nuclear translocator-like, also known as ARNTL, Bmal1, or Mop3, is a gene.

The protein encoded by this gene is a basic-helix-loop-helix PAS (bHLH-PAS) domain containing protein that forms a heterodimer with a second bHLH-PAS protein, Clock, or its ortholog, Npas2. This complex binds to E-box response elements in promoter regions of many genes including two families of repressor proteins, the Per genes (Per1, Per2, Per3) and the Cryptochromes  (Cry1 and Cry2). These repressor proteins are translated, and bind in a complex with casein kinase one epsilon (Csnk1e) and delta (Csnk1d). Next, the entire complex translocates to the nucleus, where it interacts with the Arntl/Clock heterodimer to inhibit its transactivation. This hypothesis is supported by the observation that point mutants in the Arntl or Clock render them resistant to interaction and repression by Cryptochromes. Transcription of Period and Cryptochrome genes, therefore, is inhibited, the protein levels of Period and Cryptochrome genes drop, and eventually repression is relieved to allow their transcription to build up again. This process occurs with a period length of approximately 24 hours.

Three transcript variants encoding two different isoforms have been found for this gene. The importance of these transcript variants is unknown.

Arntl (or Bmal1 or Mop3) is the only component of the mammalian circadian clock whose sole deletion in a mouse model generates arrhythmicity. In addition to defects in the clock, these Arntl null-mice also have reproductive problems, are small in stature, age quickly , and have progressive arthropathy that results in having less overall locomotor activity than wild type mice. Recent phenotyping data suggests that this gene and its partner Clock also play a role in regulation of glucose homeostasis and metabolism. Finally, Arntl, Npas2, and Per2 have been associated with seasonal affective disorder in humans.

Arntl transcription is circadian and reciprocally regulated by NR1D1 (Rev-erb-alpha) and RORA, which establishes a second interlocking loop in the mammalian circadian clock.