A conditional
            <i>Smg6</i>
            mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway

Katsioudi, Georgia; Dreos, René; Arpa, Enes S.; Gaspari, Sevasti; Liechti, Angélica; Sato, Miho; Gabriel, Christian; Kramer, Achim; Brown, Steven A.; Gatfield, David

doi:10.1126/sciadv.ade2828

Cited by 9 publications

(29 citation statements)

References 74 publications

(127 reference statements)

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“…FMRP acts as an NMD repressor in neural cells and in its absence, NMD is hyperactivated, leading to widespread transcriptome changes which contributes to intellectual disability and autism (Kurosaki et al, 2021). Recently, a conditional Smg6 mutant mouse model revealed that the NMD pathway has a role in controlling circadian clock regulation (Katsioudi et al, 2023).…”

Section: Nmd Regulationmentioning

confidence: 99%

Translation‐coupled mRNA quality control mechanisms

Monaghan,

Longman,

Cáceres

2023

The EMBO Journal

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AbstractmRNA surveillance pathways are essential for accurate gene expression and to maintain translation homeostasis, ensuring the production of fully functional proteins. Future insights into mRNA quality control pathways will enable us to understand how cellular mRNA levels are controlled, how defective or unwanted mRNAs can be eliminated, and how dysregulation of these can contribute to human disease. Here we review translation‐coupled mRNA quality control mechanisms, including the non‐stop and no‐go mRNA decay pathways, describing their mechanisms, shared trans‐acting factors, and differences. We also describe advances in our understanding of the nonsense‐mediated mRNA decay (NMD) pathway, highlighting recent mechanistic findings, the discovery of novel factors, as well as the role of NMD in cellular physiology and its impact on human disease.

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Section: Nmd Regulationmentioning

confidence: 99%

Translation‐coupled mRNA quality control mechanisms

Monaghan,

Longman,

Cáceres

2023

The EMBO Journal

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“…(D) Expression plots for around-the-clock RNA-seq data from [29] for Tfrc showing mRNA (top panel; exonic reads) and pre-mRNA (bottom panel; intronic reads) for Smg6 mutants (yellow) and controls (blue). RPKM values (reads per kilobase of transcript per million mapped reads) of individual mouse livers are shown as dots with solid lines connecting the means across time points.…”

Section: Resultsmentioning

confidence: 99%

“…The other analysed dataset (Fig. 2D) contained a matching cohort of animals that expressed a catalytically inactive, mutant version of the endonuclease SMG6; this enzyme degrades transcripts targeted through the nonsense-mediated decay (NMD) pathway [29]. Interestingly, at all timepoints Tfrc mRNA abundances were post-transcriptionally increased in Smg6 mutant livers, leading to >2-fold higher mRNA levels; still, mutants showed similar rhythmicity dynamics and peak-to-trough amplitudes in the range of ca.…”

Section: Resultsmentioning

confidence: 99%

Section: Rhythmic Abundance Of 3' Ire-containingmentioning

confidence: 99%

“…RPKM values (reads per kilobase of transcript per million mapped reads) of individual mouse livers are shown as dots with solid lines connecting the means across time points. Dashed lines represent rhythmic curve fittings to the data, as described in [29].…”

Section: In Vivo Recording In the Rt-biolumicordermentioning

confidence: 99%

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Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

Nadimpalli,

Katsioudi,

Arpa

et al. 2023

Preprint

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A central mechanism for cellular iron homeostasis involves iron regulatory proteins, IRP1 and IRP2, that interact with iron regulatory elements (IREs) on mRNAs. IRPs act as sensors of metabolic cues (foremost of iron itself) and can regulate either translation or transcript stability, depending on IRE location within the mRNA. In liver, IRP2 is widely considered the principle player mediating IRE regulation. Here, we uncover high-amplitude diurnal rhythms in the regulation of several prominent IRE-containing mRNAs in liver, compatible with maximal IRP activity at the onset of the dark phase of the day (a timepoint likely underrepresented in previous studies on IRP/IRE regulation). We find that IRP2 protein abundance itself oscillates over the day, yet ribosome profiling in livers from IRP2-deficient mice uncovers that IRP2 is dispensable for maximal repression of its rhythmically regulated target mRNAs at the time of its highest abundance, i.e. the light-dark transition. These findings are compatible with temporally controlled redundancy in IRP activities, with IRP2 exclusively mediating regulation of IRE-containing transcripts in the light phase and redundancy, conceivably with IRP1, at dark onset. We further unveil that the identified diurnal IRP/IRE regulation can ensue in the absence of a functional circadian clock as long as feeding is rhythmic, and that it follows feeding rhythms also in the presence of a clock, thus identifying feeding-associated signals as the dominant driver of IRP/IRE rhythmicity. Altogether, our study identifies a novel level of regulatory control and complexity in a metabolic pathway that had been considered well-understood since a long time.

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Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis

Alkhoury,

Henneman,

Petrenko

et al. 2023

Nat Cell Biol

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Metabolic demands fluctuate rhythmically and rely on coordination between the circadian clock and nutrient-sensing signalling pathways, yet mechanisms of their interaction remain not fully understood. Surprisingly, we find that class 3 phosphatidylinositol-3-kinase (PI3K), known best for its essential role as a lipid kinase in endocytosis and lysosomal degradation by autophagy, has an overlooked nuclear function in gene transcription as a coactivator of the heterodimeric transcription factor and circadian driver Bmal1–Clock. Canonical pro-catabolic functions of class 3 PI3K in trafficking rely on the indispensable complex between the lipid kinase Vps34 and regulatory subunit Vps15. We demonstrate that although both subunits of class 3 PI3K interact with RNA polymerase II and co-localize with active transcription sites, exclusive loss of Vps15 in cells blunts the transcriptional activity of Bmal1–Clock. Thus, we establish non-redundancy between nuclear Vps34 and Vps15, reflected by the persistent nuclear pool of Vps15 in Vps34-depleted cells and the ability of Vps15 to coactivate Bmal1–Clock independently of its complex with Vps34. In physiology we find that Vps15 is required for metabolic rhythmicity in liver and, unexpectedly, it promotes pro-anabolic de novo purine nucleotide synthesis. We show that Vps15 activates the transcription of Ppat, a key enzyme for the production of inosine monophosphate, a central metabolic intermediate for purine synthesis. Finally, we demonstrate that in fasting, which represses clock transcriptional activity, Vps15 levels are decreased on the promoters of Bmal1 targets, Nr1d1 and Ppat. Our findings open avenues for establishing the complexity for nuclear class 3 PI3K signalling for temporal regulation of energy homeostasis.

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A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway

Cited by 9 publications

References 74 publications

Translation‐coupled mRNA quality control mechanisms

Translation‐coupled mRNA quality control mechanisms

Diurnal control of iron responsive element containing mRNAs through iron regulatory proteins IRP1 and IRP2 is mediated by feeding rhythms

Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis

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