| Autor: |
Katsioudi G; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Dreos R; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Arpa ES; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Gaspari S; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Liechti A; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland., Sato M; Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., Gabriel CH; Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Laboratory of Chronobiology, Berlin, Germany., Kramer A; Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Laboratory of Chronobiology, Berlin, Germany., Brown SA; Chronobiology and Sleep Research Group, Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland., Gatfield D; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland. |
| Abstrakt: |
Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We find that NMD down-regulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. Specifically, we uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. Transcriptome-wide changes in daily mRNA accumulation patterns in the entrained liver, as well as an altered response to food entrainment, expand the known scope of NMD regulation in mammalian gene expression and physiology. |
