Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

Oct 22, 2015Genome research

Rhythmic protein production in the liver and daily clock control by regulatory sequences before genes

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Abstract

Approximately 150 mRNAs show robust daily changes in translation efficiency in mouse liver.

Extensive rhythms in ribosome occupancy were observed across the transcriptome.
Cycling proteins from nonoscillating transcripts display rhythmic regulation linked to specific pathways, particularly in iron metabolism.
Estimates of core clock protein biosynthesis from translation data provided better explanations for circadian clock features than mRNA expression alone.
Translated upstream open reading frames (uORFs) were identified as a novel regulatory mechanism within the circadian clock.
Loss-of-function of the Denr protein, which is involved in uORF regulation, resulted in a shortening of the circadian period in cells.

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Mammalian gene expression displays widespread circadian oscillations. Rhythmic transcription underlies the core clock mechanism, but it cannot explain numerous observations made at the level of protein rhythmicity. We have used ribosome profiling in mouse liver to measure the translation of mRNAs into protein around the clock and at high temporal and nucleotide resolution. We discovered, transcriptome-wide, extensive rhythms in ribosome occupancy and identified a core set of approximately 150 mRNAs subject to particularly robust daily changes in translation efficiency. Cycling proteins produced from nonoscillating transcripts revealed thus-far-unknown rhythmic regulation associated with specific pathways (notably in iron metabolism, through the rhythmic translation of transcripts containing iron responsive elements), and indicated feedback to the rhythmic transcriptome through novel rhythmic transcription factors. Moreover, estimates of relative levels of core clock protein biosynthesis that we deduced from the data explained known features of the circadian clock better than did mRNA expression alone. Finally, we identified uORF translation as a novel regulatory mechanism within the clock circuitry. Consistent with the occurrence of translated uORFs in several core clock transcripts, loss-of-function of Denr, a known regulator of reinitiation after uORF usage and of ribosome recycling, led to circadian period shortening in cells. In summary, our data offer a framework for understanding the dynamics of translational regulation, circadian gene expression, and metabolic control in a solid mammalian organ.

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Ribosome profiling reveals the rhythmic liver translatome and circadian clock regulation by upstream open reading frames

Abstract

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