The circadian clock and feeding rhythms are both important regulators of rhythmic gene expression in the liver. To further dissect the respective contributions of feeding and the clock, we analyzed differential rhythmicity of liver tissue samples across several conditions. We developed a statistical method tailored to compare rhythmic liver messenger RNA (mRNA) expression in mouse knockout models of multiple clock genes, as well as PARbZip output transcription factors (Hlf/Dbp/Tef). Mice were exposed to ad libitum or night-restricted feeding under regular light–dark cycles. During ad libitum feeding, genetic ablation of the core clock attenuated rhythmic-feeding patterns, which could be restored by the night-restricted feeding regimen. High-amplitude mRNA expression rhythms in wild-type livers were driven by the circadian clock, but rhythmic feeding also contributed to rhythmic gene expression, albeit with significantly lower amplitudes. We observed that Bmal1 and Cry1/2 knockouts differed in their residual rhythmic gene expression. Differences in mean expression levels between wild types and knockouts correlated with rhythmic gene expression in wild type. Surprisingly, in PARbZip knockout mice, the mean expression levels of PARbZip targets were more strongly impacted than their rhythms, potentially due to the rhythmic activity of the D-box–repressor NFIL3. Genes that lost rhythmicity in PARbZip knockouts were identified to be indirect targets. Our findings provide insights into the diurnal transcriptome in mouse liver as we identified the differential contributions of several core clock regulators. In addition, we gained more insights on the specific effects of the feeding–fasting cycle.

生物钟和进食节律都是肝脏节律性基因表达的重要调节因子。为了进一步剖析喂养和时钟各自的贡献，我们分析了几种条件下肝组织样本的不同节律性。我们开发了一种统计方法，用于比较多个时钟基因的小鼠敲除模型中的节律性肝脏信使 RNA (mRNA) 表达，以及 PARbZip 输出转录因子 ( Hlf / Dbp / Tef）。小鼠在规律的明暗循环下随意进食或夜间限制进食。在随意喂养期间，核心时钟的基因消融减弱了节律性喂养模式，这可以通过夜间限制喂养方案恢复。野生型肝脏中的高幅度 mRNA 表达节律由生物钟驱动，但节律性喂养也有助于节律性基因表达，尽管幅度明显较低。我们观察到Bmal1和Cry1 / 2敲除的残留节律基因表达不同。野生型和敲除之间平均表达水平的差异与野生型中的节律性基因表达相关。令人惊讶的是，在 PARbZip 敲除小鼠中，PARbZip 靶标的平均表达水平受到的影响比它们的节律更强烈，这可能是由于 D-box 阻遏物 NFIL3 的节律活性所致。在 PARbZip 敲除中失去节律性的基因被确定为间接目标。我们的研究结果提供了对小鼠肝脏昼夜转录组的见解，因为我们确定了几个核心时钟调节器的不同贡献。此外，我们对进食-禁食周期的具体影响有了更多的了解。