Remodeling of the hepatic circadian transcriptome across the estrous cycle

The circadian clock system drives rhythms in gene expression, tailoring an organism's behavior and physiology to the ∼24-hour day-night environmental cycle. The mechanisms underlying this system are believed to be largely the same between adult males and females, but recent findings are starting to challenge this notion. Menstrual/estrous cycles (e-cycles) in females modulate a variety of circadian-controlled behaviors, but how they may interact with rhythmicity at the system level are an unknown but vital dimension in circadian biology in females. To start bridging this gap, we explored the circadian transcriptome of the mouse liver across the four phases of the 'free-running' e-cycle. Much to our surprise, we found that the e-cycle imposes a∼4-day rhythm in the 24-hour rhythmicity of a considerable proportion of the circadian transcriptome, with the largest differences in rhythmicity occurring between pre- and post-ovulation phases. These differences also appear highly time-of-day dependent, and gene promotor analysis suggests that both e-cycle and sex dependent rhythmicity may be due to relatively simplistic mechanisms, possibly involving the action of core circadian transcription factors on output genes. Taken together, this study establishes that the estrous cycle modulates circadian gene expression in the liver, suggesting that circadian system has evolved specific mechanisms tailored to the different needs of males and females in their normal daily environments.