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Cell Metab. 2018 Feb 6;27(2):404-418.e7. doi: 10.1016/j.cmet.2017.12.010. Epub 2018 Jan 18.

The RNA-Binding Protein NONO Coordinates Hepatic Adaptation to Feeding.

Author information

1
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.
2
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
3
The Razavi Newman Integrative Genomics and Bioinformatics Core Facility, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
4
Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
5
Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland. Electronic address: steven.brown@pharma.uzh.ch.
6
Regulatory Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address: satchin@salk.edu.

Abstract

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.

KEYWORDS:

DBHS protein; NOPS protein; circadian clock; diabetes; metabolic disorder; paraspeckle

PMID:
29358041
DOI:
10.1016/j.cmet.2017.12.010

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