Société des Produits Nestlé, Nestlé Research, CH-1015 Lausanne, Switzerland.
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Proc Natl Acad Sci U S A. 2021 Jan 19;118(3). doi: 10.1073/pnas.2015803118.
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 (//). 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 and / 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中节律性基因表达的重要调节因子。为了进一步剖析进食和生物钟各自的贡献,我们分析了几种条件下肝脏组织样本的差异节律性。我们开发了一种统计方法,专门用于比较多个生物钟基因敲除小鼠模型中肝脏信使 RNA(mRNA)表达的节律性,以及 PARbZip 输出转录因子(//)。小鼠在常规光照-黑暗周期下进行随意或夜间限制进食。在随意进食时,核心生物钟的遗传缺失减弱了节律性进食模式,而夜间限制进食方案可以恢复这些模式。野生型肝脏中高振幅的 mRNA 表达节律由生物钟驱动,但节律性进食也有助于基因表达的节律性,尽管幅度明显较低。我们观察到和//敲除小鼠在剩余的节律性基因表达方面存在差异。野生型和敲除型之间的平均表达水平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 靶基因的平均表达水平受影响比其节律性更为显著,这可能是由于 D 盒抑制剂 NFIL3 的节律性活性。在 PARbZip 敲除小鼠中失去节律性的基因被鉴定为间接靶基因。我们的研究结果为我们确定了几个核心生物钟调节剂的差异贡献,提供了对小鼠肝脏昼夜转录组的深入了解。此外,我们对禁食-进食周期的具体影响有了更深入的认识。