Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland; Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Cell Metab. 2018 Feb 6;27(2):404-418.e7. doi: 10.1016/j.cmet.2017.12.010. Epub 2018 Jan 18.
The mechanisms by which feeding and fasting drive rhythmic gene expression for physiological adaptation to daily rhythm in nutrient availability are not well understood. Here we show that, upon feeding, the RNA-binding protein NONO accumulates within speckle-like structures in liver cell nuclei. Combining RNA-immunoprecipitation and sequencing (RIP-seq), we find that an increased number of RNAs are bound by NONO after feeding. We further show that NONO binds and regulates the rhythmicity of genes involved in nutrient metabolism post-transcriptionally. Finally, we show that disrupted rhythmicity of NONO target genes has profound metabolic impact. Indeed, NONO-deficient mice exhibit impaired glucose tolerance and lower hepatic glycogen and lipids. Accordingly, these mice shift from glucose storage to fat oxidation, and therefore remain lean throughout adulthood. In conclusion, our study demonstrates that NONO post-transcriptionally coordinates circadian mRNA expression of metabolic genes with the feeding/fasting cycle, thereby playing a critical role in energy homeostasis.
进食和禁食驱动生理适应营养可用性日常节律的节律基因表达的机制尚不清楚。在这里，我们表明，进食时，RNA 结合蛋白 NONO 在肝细胞核的斑点样结构内积累。通过 RNA 免疫沉淀和测序 (RIP-seq)，我们发现进食后 NONO 结合的 RNA 数量增加。我们进一步表明 NONO 结合并调节参与营养代谢的基因的节律性转录后。最后，我们表明 NONO 靶基因节律性的破坏会产生深远的代谢影响。事实上，NONO 缺陷小鼠表现出葡萄糖耐量受损和肝糖原和脂质水平降低。因此，这些小鼠从葡萄糖储存转变为脂肪氧化，因此在整个成年期保持苗条。总之，我们的研究表明，NONO 在后转录水平上协调代谢基因的生物钟 mRNA 表达与进食/禁食周期，从而在能量平衡中发挥关键作用。
