Ribosome profiling reveals an important role for translational control in circadian gene expression

Jang, Christopher J.; Lahens, Nicholas F.; Hogenesch, John B.; Sehgal, Amita

doi:10.1101/gr.191296.115

Cited by 94 publications

(127 citation statements)

References 74 publications

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“…These data lead to additional questions: (i) To what extent does clock control of translation elongation affect rhythmic protein levels, and (ii) what is the advantage of clock control of translation elongation to the organism? Recent ribosome profiling in mammalian cells revealed that ∼10% of mRNAs with rhythmic ribosome occupancy lacked corresponding rhythmic mRNA levels (56,57). In the mouse liver, rhythmic ribosome occupancy on ∼500 constitutively accumulating mRNAs was enriched for mRNAs containing 5′-Terminal Oligo Pyrimidine (TOP) tracts, or Translation Initiator of Short 5′-UTR (TISU) elements (58).…”

Section: Discussionmentioning

confidence: 99%

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Caster

Castillo

Sachs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. In Neurospora crassa, the circadian clock generates daily rhythms in the activation of conserved mitogen-activated protein kinase (MAPK) pathways when cells are grown in constant conditions, including rhythmic activation of the well-characterized p38 osmosensing (OS) MAPK pathway. Rhythmic phosphorylation of the MAPK OS-2 (P-OS-2) leads to temporal control of downstream targets of OS-2. We show that osmotic stress in N. crassa induced the phosphorylation of a eukaryotic elongation factor-2 (eEF-2) kinase, radiation sensitivity complementing kinase-2 (RCK-2), and that RCK-2 is necessary for high-level phosphorylation of eEF-2, a key regulator of translation elongation. The levels of phosphorylated RCK-2 and phosphorylated eEF-2 cycle in abundance in wild-type cells but not in cells deleted for OS-2 or the core clock component FREQUENCY (FRQ). Translation extracts from cells grown in constant conditions show decreased translational activity in the late subjective morning, coincident with the peak in eEF-2 phosphorylation, and rhythmic translation of glutathione S-transferase (GST-3) from constitutive mRNA levels in vivo is dependent on circadian regulation of eEF-2 activity. In contrast, rhythms in phosphorylated eEF-2 levels are not necessary for rhythms in accumulation of the clock protein FRQ, indicating that clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs.C ircadian rhythms are the outward manifestation of an endogenous clock mechanism common to nearly all eukaryotes. Depending on the organism and tissue, nearly half of an organism's expressed genes are under control of the circadian clock at the level of transcription (1-4). However, mounting evidence indicates a role for the clock in controlling posttranscriptional mechanisms (5), including translation initiation (6, 7), whereas clock control of translation elongation has not been investigated.The driver of circadian rhythms in Neurospora crassa is an autoregulatory molecular feedback loop composed of the negative elements FREQUENCY (FRQ) and FRQ RNA-interacting helicase (FRH), which inhibit the activity of the positive elements WHITE COLLAR-1 (WC-1) and WC-2 (8-11). WC-1 and WC-2 heterodimerize to form the white collar complex (WCC), which activates transcription of frequency (frq) (8,12,13) and activates transcription of a large set of downstream target genes important for overt rhythmicity (2, 14). One gene directly controlled by the WCC is os-4, which encodes the mitogen-activated protein kinase kinase kinase (MAPKKK) in the osmotically sensitive (OS) MAPK pathway (15). Rhythmic transcription of os-4 leads to rhythmic accumulation of the phosphorylated active form of the downstream p38-like mitogen-activated protein kinase (MAPK) OS-2 (16). In Sac...

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Section: Discussionmentioning

confidence: 99%

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Caster

Castillo

Sachs

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Translation efficiency is estimated by comparing ribosomal occupancy to transcript abundance. This approach was applied to human cell line (Jang et al 2015) and mouse liver around the clock (Atger et al 2015;Janich et al 2015). The results suggested that, for most genes, when transcription fluctuates in a circadian manner, mRNA accumulation and protein synthesis follows.…”

Section: Circadian Regulation In Translation Efficiencymentioning

confidence: 99%

“…Protein synthesis can be rhythmic from mRNAs whose abundances are constant. Conversely, mRNA abundance can be rhythmic but lead to flat ribosomal occupancy (Atger et al 2015;Jang et al 2015;Janich et al 2015). For example, iron metabolism mRNAs accumulate constantly but are rhythmically translated in mouse liver (Janich et al 2015).…”

Section: Circadian Regulation In Translation Efficiencymentioning

confidence: 99%

“…A remarkable observation in mouse liver and human cells is the presence of upstream open reading frame (uORFs) in core clock mRNAs (Jang et al 2015;Janich et al 2015). Although the functions of the short peptides translated from these uORFs are unknown, disruption of translation reinitiation perturbed the circadian period length of mouse fibroblast (Janich et al 2015).…”

Section: Circadian Regulation In Translation Efficiencymentioning

confidence: 99%

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Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

Yeung

Naef

2016

Cold Spring Harb Perspect Biol

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Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level. In this review, we introduce some basic concepts underlying periodicity of gene regulation, and then highlight recent genome-wide investigations on the propagation of rhythms across multiple regulatory layers in mammals, all the way from chromatin conformation to protein accumulation.

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“…The mutant cells cannot limit the abundance of the transcriptional repressor Yox1, likely because PBs fail to repress properly the translation of Yox1 mRNA. Interestingly, the circadian clock controls PB formation [35]. Thus, it is possible that DNA repair or regulatory switches associated with PBs undergo rhythmic changes.…”

Section: Rna Granules Generated In the Absence Of Stressmentioning

confidence: 99%

Cytoplasmic RNA Granules in Somatic Maintenance

Moujaber¹,

Stochaj²

2018

Gerontology

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Cytoplasmic RNA granules represent subcellular compartments that are enriched in protein-bound RNA species. RNA granules are produced by evolutionary divergent eukaryotes, including yeast, mammals, and plants. The functions of cytoplasmic RNA granules differ widely. They are dictated by the cell type and physiological state, which in turn is determined by intrinsic cell properties and environmental factors. RNA granules provide diverse cellular functions. However, all of the granules contribute to aspects of RNA metabolism. This is exemplified by transcription, RNA storage, silencing, and degradation, as well as mRNP remodeling and regulated translation. Several forms of cytoplasmic mRNA granules are linked to normal physiological processes. For instance, they may coordinate protein synthesis and thereby serve as posttranscriptional “operons”. RNA granules also participate in cytoplasmic mRNA trafficking, a process particularly well understood for neurons. Many forms of RNA granules support the preservation of somatic cell performance under normal and stress conditions. On the other hand, severe insults or disease can cause the formation and persistence of RNA granules that contribute to cellular dysfunction, especially in the nervous system. Neurodegeneration and many other diseases linked to RNA granules are associated with aging. Nevertheless, information related to the impact of aging on the various types of RNA granules is presently very limited. This review concentrates on cytoplasmic RNA granules and their role in somatic cell maintenance. We summarize the current knowledge on different types of RNA granules in the cytoplasm, their assembly and function under normal, stress, or disease conditions. Specifically, we discuss processing bodies, neuronal granules, stress granules, and other less characterized cytoplasmic RNA granules. Our focus is primarily on mammalian and yeast models, because they have been critical to unravel the physiological role of various RNA granules. RNA granules in plants and pathogens are briefly described. We conclude our viewpoint by summarizing the emerging concepts for RNA granule biology and the open questions that need to be addressed in future studies.

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Ribosome profiling reveals an important role for translational control in circadian gene expression

Cited by 94 publications

References 74 publications

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World

Cytoplasmic RNA Granules in Somatic Maintenance

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