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 are known to modulate a variety of circadian-controlled behaviors. However, their interaction with circadian rhythmicity at the transcriptional level remains unknown. To assess the interaction between e-cycles and the circadian clock, we explored densely collected mouse liver circadian transcriptomes across all four phases of the e-cycle. Surprisingly, we found that the circadian rhythmicity in female livers was strikingly dependent on e-cycle phase, with the largest differences aligning with pre- and post-ovulation. The differential rhythmicity followed prominent yet distinct patterns, which extend and diversify overall sex differences in rhythmic gene expression. Our data also predict that sex and e-cycle may modulate how core circadian transcription factors may regulate expression of some output genes, but other mechanisms appear complex and potentially multifaceted. Nonetheless, the differences in rhythmicity impact broad aspects of liver function, making this panoramic dataset a novel resource for identifying and exploring novel interactions of the estrous cycle on gene expression and overall liver functions.