Isoform-specific regulation of rhythmic gene expression by alternative polyadenylation

Greenwell, Ben J.; Beytebiere, Joshua R.; Lamb, Teresa M.; Bell-Pedersen, Deborah; Merlin, Christine; Menet, Jérôme S.

doi:10.1101/2020.12.12.422514

Cited by 7 publications

(6 citation statements)

References 109 publications

(149 reference statements)

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“…Circadian control of polyadenylation is an emerging topic. Modern transcriptomic approaches have identified hundreds of rhythmic APA events in mice and in plants [111][112][113][114]. We and others have begun to define the set of APA events in Neurospora [65] (S3 Table ), which can be extended to circadian APA events.…”

Section: Plos Biology Fig)mentioning

confidence: 99%

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

et al. 2023

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Compensation is a defining principle of a true circadian clock, where its approximately 24-hour period length is relatively unchanged across environmental conditions. Known compensation effectors directly regulate core clock factors to buffer the oscillator’s period length from variables in the environment. Temperature Compensation mechanisms have been experimentally addressed across circadian model systems, but much less is known about the related process of Nutritional Compensation, where circadian period length is maintained across physiologically relevant nutrient levels. Using the filamentous fungus Neurospora crassa, we performed a genetic screen under glucose and amino acid starvation conditions to identify new regulators of Nutritional Compensation. Our screen uncovered 16 novel mutants, and together with 4 mutants characterized in prior work, a model emerges where Nutritional Compensation of the fungal clock is achieved at the levels of transcription, chromatin regulation, and mRNA stability. However, eukaryotic circadian Nutritional Compensation is completely unstudied outside of Neurospora. To test for conservation in cultured human cells, we selected top hits from our fungal genetic screen, performed siRNA knockdown experiments of the mammalian orthologs, and characterized the cell lines with respect to compensation. We find that the wild-type mammalian clock is also compensated across a large range of external glucose concentrations, as observed in Neurospora, and that knocking down the mammalian orthologs of the Neurospora compensation-associated genes CPSF6 or SETD2 in human cells also results in nutrient-dependent period length changes. We conclude that, like Temperature Compensation, Nutritional Compensation is a conserved circadian process in fungal and mammalian clocks and that it may share common molecular determinants.

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Section: Plos Biology Fig)mentioning

confidence: 99%

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

et al. 2023

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“…4. Mus musculus (mouse): data from GSE115553 (Graham et al, 2018), GSE151173 (Greenwell et al, 2020), and GSE171975 (Aviram et al, 2021) were aggregated into a gene expression dataset with 208 training samples and 121 testing samples. 5.…”

Section: Rna Sequencing Data Usedmentioning

confidence: 99%

Bipartite networks represent causality better than simple networks: evidence, algorithms, and applications

Shen,

Coruzzi,

Shasha

2024

Front. Genet.

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A network, whose nodes are genes and whose directed edges represent positive or negative influences of a regulatory gene and its targets, is often used as a representation of causality. To infer a network, researchers often develop a machine learning model and then evaluate the model based on its match with experimentally verified “gold standard” edges. The desired result of such a model is a network that may extend the gold standard edges. Since networks are a form of visual representation, one can compare their utility with architectural or machine blueprints. Blueprints are clearly useful because they provide precise guidance to builders in construction. If the primary role of gene regulatory networks is to characterize causality, then such networks should be good tools of prediction because prediction is the actionable benefit of knowing causality. But are they? In this paper, we compare prediction quality based on “gold standard” regulatory edges from previous experimental work with non-linear models inferred from time series data across four different species. We show that the same non-linear machine learning models have better predictive performance, with improvements from 5.3% to 25.3% in terms of the reduction in the root mean square error (RMSE) compared with the same models based on the gold standard edges. Having established that networks fail to characterize causality properly, we suggest that causality research should focus on four goals: (i) predictive accuracy; (ii) a parsimonious enumeration of predictive regulatory genes for each target gene g; (iii) the identification of disjoint sets of predictive regulatory genes for each target g of roughly equal accuracy; and (iv) the construction of a bipartite network (whose node types are genes and models) representation of causality. We provide algorithms for all goals.

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“…Rhythmic APA site usage has been uncovered in the mouse liver 21,22,53 , and in temperatureentrained cultured cells, circadian APA usage occurs in many genes and can regulate expression of speci c central clock genes 23 . Still, alternative poly(A) site usage hasn't been given enough attention.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, there's growing evidence of cell-type-speci c APA preference 20 . The involvement of APA in the context of sleep and circadian rhythms has been largely unexplored, with the few studies available mostly focused on peripheral organs 21,22 and cells 23 . Here, we have characterized how APA site usage oscillates based on the time of day as well as how it is altered following acute changes in sleep pressure, speci cally in the adult mammalian brain.…”

Section: Introductionmentioning

confidence: 99%

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders

Flores,

Pasetto,

Wang

et al. 2024

Preprint

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Sleep and circadian rhythm disruptions are comorbid features of many pathologies and can negatively influence numerous health conditions, including degenerative diseases, metabolic illnesses, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. Thus, associations between sleep and/or circadian rhythm and alternative polyadenylation (APA), particularly in the context of other health challenges, are largely undescribed. APA is a process that generates various transcript isoforms from the same gene, resulting in effects on mRNA translation, stability, localization, and subsequent function. Here, we have identified unique APAs in rat brain that exhibit time-of-day-dependent oscillations in expression as well as APAs that are altered by sleep deprivation and the subsequent recovery period. Genes affected by APA usage include Mapt/Tau, Ntrk2, Homer1A, Sin3band Sorl. Sorl1 has two APAs which cycle with a 24 h period, one additional APA cycles with a 12 h period and one more that is reduced during recovery sleep. Finally, we compared sleep- or circadian-associated APAs with recently described APA-linked brain disorder susceptibility genes and found 46 genes in common.

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Isoform-specific regulation of rhythmic gene expression by alternative polyadenylation

Cited by 7 publications

References 109 publications

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

Nutritional compensation of the circadian clock is a conserved process influenced by gene expression regulation and mRNA stability

Bipartite networks represent causality better than simple networks: evidence, algorithms, and applications

Identification of sleep and circadian alternative polyadenylation sites associated with APA-linked human brain disorders

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