A role for gene expression and mRNA stability in nutritional compensation of the circadian clock
Ontology highlight
ABSTRACT:
ORGANISM(S): Neurospora crassa
PROVIDER: GSE201901 | GEO | 2022/12/16
REPOSITORIES: GEO
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Project description: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.
| S-EPMC9848017 | biostudies-literature
Project description:Mutants in the period-1 (prd-1) gene, characterized by a recessive allele, display a reduced growth rate and period lengthening of the developmental cycle controlled by the circadian clock. We refined the genetic location of prd-1 and used whole genome sequencing to find the mutation defining it, confirming the identity of prd-1 by rescuing the mutant circadian phenotype via transformation. PRD-1 is an RNA helicase whose orthologs, DDX5 [DEAD (Asp-Glu-Ala-Asp) Box Helicase 5] and DDX17 in humans and DBP2 (Dead Box Protein 2) in yeast, are implicated in various processes, including transcriptional regulation, elongation, and termination, ribosome biogenesis, and mRNA decay. Although prd-1 mutants display a long period (∼25 h) circadian developmental cycle, they interestingly display a WT period when the core circadian oscillator is tracked using a frq-luciferase transcriptional fusion under conditions of limiting nutritional carbon; the core oscillator in the prd-1 mutant strain runs with a long period under glucose-sufficient conditions. Thus, PRD-1 clearly impacts the circadian oscillator and is not only part of a metabolic oscillator ancillary to the core clock. PRD-1 is an essential protein, and its expression is neither light-regulated nor clock-regulated. However, it is transiently induced by glucose; in the presence of sufficient glucose, PRD-1 is in the nucleus until glucose runs out, which elicits its disappearance from the nucleus. Because circadian period length is carbon concentration-dependent, prd-1 may be formally viewed as a clock mutant with defective nutritional compensation of circadian period length.
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Project description:Tseng2012 - Circadian clock of N.crassa
A comprehensive model of the circardian clock of fungal Neurospora crassa
, which encompasses existing knowledge of the biochemistry of Neurospora clock, is described by Tseng et al.
(2012). The model is validated against a wide range of experimental phenotypes and has been used to investigate possible molecular explanations of temperature compensation.
This model is described in the article:
Comprehensive modelling of the Neurospora circadian clock and its temperature compensation.
Tseng YY, Hunt SM, Heintzen C, Crosthwaite SK, Schwartz JM
PLoS Comput. Biol. [2012 ; Volume: 8 (Issue: 3 )] Page info: e1002437
Abstract:
Circadian clocks provide an internal measure of external time allowing organisms to anticipate and exploit predictable daily changes in the environment. Rhythms driven by circadian clocks have a temperature compensated periodicity of approximately 24 hours that persists in constant conditions and can be reset by environmental time cues. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock phenotypes. Here we present a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, arrhythmicity in constant light, resetting by brief light pulses, and entrainment to full photoperiods. Crucial components influencing the period and amplitude of oscillations were identified by control analysis. Furthermore, simulations enabled us to propose a mechanism for temperature compensation, which is achieved by simultaneously increasing the translation of frq RNA and decreasing the nuclear import of FRQ protein.
Figure 3 of the reference publication has been reproduced using Copasi 4.8 (Build 35).
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2024-09-02 | BIOMD0000000437 | BioModels
Project description:We report the genome-wide impact of rhythmic P-eIF2α levels in vivo by performing ribosome profiling and RNA-seq in Neurospora crassa samples grown over a circadian time course. We identified candidate genes which showed rhyhmic ribosome occupancy in WT cells but lost rhythms in mRNA levels and ribosome occupancy in the clock mutant Dfrq, eIF2α kinase knockout Dcpc-3, and constitutively active kinase mutant cpc-3c cells. Select mRNAs harbor a P-body localization motif identified by MEME and MEME Suite's GOMo function. P-body localization of the target mRNAs provides an attractive mechanism for explaining translational rhythms from otherwise arrhythmic mRNAs.
2022-09-23 | GSE181565 | GEO
Project description:We report the genome-wide impact of rhythmic P-eIF2α levels in vivo by performing ribosome profiling and RNA-seq in Neurospora crassa samples grown over a circadian time course. We identified candidate genes which showed rhyhmic ribosome occupancy in WT cells but lost rhythms in mRNA levels and ribosome occupancy in the clock mutant Dfrq, eIF2α kinase knockout Dcpc-3, and constitutively active kinase mutant cpc-3c cells. Select mRNAs harbor a P-body localization motif identified by MEME and MEME Suite's GOMo function. P-body localization of the target mRNAs provides an attractive mechanism for explaining translational rhythms from otherwise arrhythmic mRNAs.
2022-09-23 | GSE181564 | GEO
Project description:Cleavage factor I mammalian (CFIm) complex, composed of cleavage and polyadenylation specificity factor CPSF6, regulates alternative polyadenylation (APA). CPSF6 has a RS-like domain which plays role in protein -protein interactions. This interaction might have role in alternative polyadenylation site selection. The phosphorylation of RS- like domain might play role in protein -protein interaction and thus might have a role in alternative polyadenylation site selection. So we did mass specteroanalysis to analyse phosphorylation sites of RS-like domain of CPSF6.
2019-04-01 | PXD012713 | Pride
Project description:Circadian rhythms and cellular metabolism are intimately linked. Here, we reveal that a high-fat diet (HFD) generates a profound reorganization of specific metabolic pathways, leading to widespread remodeling of the liver clock. Strikingly, in addition to disrupting the normal circadian cycle, HFD causes an unexpectedly large-scale genesis of de novo oscillating transcripts, resulting in reorganization of the coordinated oscillations between coherent transcripts and metabolites. The mechanisms underlying this reprogramming involve both the impairment of CLOCK:BMAL1 chromatin recruitment and a pronounced cyclic activation of surrogate pathways through the transcriptional regulator PPAR?. Finally, we demonstrate that it is specifically the nutritional challenge, and not the development of obesity, that causes the reprogramming of the clock and that the effects of the diet on the clock are reversible.
| S-EPMC4573395 | biostudies-literature
Project description:Many fungi form complex three-dimensional fruiting bodies, within which the meiotic machinery for sexual spore production has been considered to be largely conserved over evolutionary time. Indeed, much of what we know about meiosis in plant and animal taxa has been deeply informed by studies of meiosis in Saccharomyces and Neurospora. Nevertheless, the genetic basis of fruiting body development and its regulation in relation to meiosis in fungi is barely known, even within the best studied multicellular fungal model Neurospora crassa. We characterized morphological development and genome-wide transcriptomics in the closely related species Neurospora crassa, Neurospora tetrasperma, and Neurospora discreta, across eight stages of sexual development. Despite diverse life histories within the genus, all three species produce vase-shaped perithecia. Transcriptome sequencing provided gene expression levels of 2479 orthologous genes among all three species. Expression of key meiosis genes and sporulation genes, corresponded to developmental differences among these Neurospora species during sexual development. Screening N. crassa knockout crosses of genes selected for their expression differences across species, eight genes, whose functions were previously unknown, are found to be critical for the successful formation of perithecia. The absence of these genes in mutant crosses resulted in either no perithecium formation or in arrested development at an early stage. Our results provide insight into the genetic basis of Neurospora sexual reproduction, which is also of great importance with regard to other multicelluar ascomycetes, including fungal pathogens closely related to Neurospora in the Sordariomycetes, such as Fusarium spp, Magnaporthe oryzae, and Nectria haematococca mRNA were sampled and compared from eight time points across sexual reproduction in three Neurospora species
2014-12-12 | E-GEOD-60256 | biostudies-arrayexpress
Project description:Many fungi form complex three-dimensional fruiting bodies, within which the meiotic machinery for sexual spore production has been considered to be largely conserved over evolutionary time. Indeed, much of what we know about meiosis in plant and animal taxa has been deeply informed by studies of meiosis in Saccharomyces and Neurospora. Nevertheless, the genetic basis of fruiting body development and its regulation in relation to meiosis in fungi is barely known, even within the best studied multicellular fungal model Neurospora crassa. We characterized morphological development and genome-wide transcriptomics in the closely related species Neurospora crassa, Neurospora tetrasperma, and Neurospora discreta, across eight stages of sexual development. Despite diverse life histories within the genus, all three species produce vase-shaped perithecia. Transcriptome sequencing provided gene expression levels of 2479 orthologous genes among all three species. Expression of key meiosis genes and sporulation genes, corresponded to developmental differences among these Neurospora species during sexual development. Screening N. crassa knockout crosses of genes selected for their expression differences across species, eight genes, whose functions were previously unknown, are found to be critical for the successful formation of perithecia. The absence of these genes in mutant crosses resulted in either no perithecium formation or in arrested development at an early stage. Our results provide insight into the genetic basis of Neurospora sexual reproduction, which is also of great importance with regard to other multicelluar ascomycetes, including fungal pathogens closely related to Neurospora in the Sordariomycetes, such as Fusarium spp, Magnaporthe oryzae, and Nectria haematococca mRNA were sampled and compared from eight time points across sexual reproduction in three Neurospora species
2014-12-12 | E-GEOD-60255 | biostudies-arrayexpress
Project description:RNA-seq from Neurospora crassa at 5 time points of light induction, with 2 replicates for each, totalling 10 samples RNA-seq from Neurospora crassa at 5 time points of light induction, with 2 replicates for each, totalling 10 samples
2014-08-01 | E-GEOD-53534 | biostudies-arrayexpress