Natural antisense transcript of regulates the amplitude of the mouse circadian clock.

In mammals, a set of core clock genes form transcription-translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the () locus that is transcribed from the antisense strand of This transcript, is expressed rhythmically and antiphasic to mRNA, leading to our hypothesis that and mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of , we found that transcription, but not transcript, represses However, does not repress as knockdown led to a decrease in the level, indicating that forms a single negative feedback loop with and maintains the level of within the oscillatory range. also regulates the amplitude of the circadian clock, and this function cannot be solely explained through its interaction with as knockdown does not recapitulate the phenotypes of perturbation. Overall, our data indicate that is an important regulatory molecule in the mammalian circadian clock machinery. Our work also supports the idea that antisense transcripts of core clock genes constitute a common feature of circadian clocks, as they are found in other organisms.