| dc.description.abstract | Nearly every mammalian cell exhibits daily rhythms in gene expression, which guide the activation of tissue-specific processes across the day. Rhythms in peripheral tissues are synchronized by neuronal and hormonal rhythmic signals as well as rhythms of body temperature and food intake, all of which originate from the master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. However, how these rhythmic signals contribute to the oscillations of gene expression and biological functions remains unknown. Increasing evidence suggests that systemic signals, and more specifically rhythmic food intake (RFI), can regulate rhythmic gene expression independently of the circadian clock. Additionally, experiments have shown that anywhere from 15-30% of the mouse hepatic transcriptome is rhythmic. However, these experiments only look at expression on an overall gene level, and so the importance of rhythmic gene expression may be understated as certain isoforms of arrhythmic genes may be rhythmic.
To determine the relative contribution of cell autonomous clocks versus RFI in the regulation of rhythmic gene expression, we developed a system that allows long-term manipulation of the daily rhythm of food intake in the mouse, and analyzed liver gene expression by RNA-Seq in mice fed ad libitum, only at night, or arrhythmically (mouse eating 1/8th of their daily food intake every 3 hours). We show that 70% of the cycling mouse liver transcriptome loses rhythmicity under arrhythmic feeding. Remarkably, this loss of rhythmic gene expression under arrhythmic feeding is independent of the liver circadian clock, which continues to exhibit normal oscillations in core clock gene expression. Together, these results demonstrate that systemic signals driven by rhythmic food intake play a more important role than the cell-autonomous circadian clock in driving rhythms in liver gene expression.
Next, to determine if alternative polyadenylation results in differential rhythmic expression of transcripts, we performed 3’-end mRNA-Seq and found that 15% of mouse hepatic transcriptome with more than one PAS exhibits differential rhythmic expression. Importantly, the major cause for this differential expression was found to be strongly related to co-transcriptional processes vs. transcriptional or post-transcriptional, and indicates that gene isoforms are independently regulated. | en |
