scholarly journals Decoupling nutrient signaling from growth rate causes aerobic glycolysis and deregulation of cell size and gene expression

2013 ◽  
Vol 24 (2) ◽  
pp. 157-168 ◽  
Author(s):  
Nikolai Slavov ◽  
David Botstein
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Cell Division ◽  
Aerobic Glycolysis ◽  
Substantial Reduction ◽  
Anaerobic Growth ◽  
Growth Media ◽  
Transcriptional Responses ◽  
Nutrient Signaling ◽  
General Signature

To survive and proliferate, cells need to coordinate their metabolism, gene expression, and cell division. To understand this coordination and the consequences of its failure, we uncoupled biomass synthesis from nutrient signaling by growing, in chemostats, yeast auxotrophs for histidine, lysine, or uracil in excess of natural nutrients (i.e., sources of carbon, nitrogen, sulfur, and phosphorus), such that their growth rates (GRs) were regulated by the availability of their auxotrophic requirements. The physiological and transcriptional responses to GR changes of these cultures differed markedly from the respective responses of prototrophs whose growth-rate is regulated by the availability of natural nutrients. The data for all auxotrophs at all GRs recapitulated the features of aerobic glycolysis, fermentation despite high oxygen levels in the growth media. In addition, we discovered wide bimodal distributions of cell sizes, indicating a decoupling between the cell division cycle (CDC) and biomass production. The aerobic glycolysis was reflected in a general signature of anaerobic growth, including substantial reduction in the expression levels of mitochondrial and tricarboxylic acid genes. We also found that the magnitude of the transcriptional growth-rate response (GRR) in the auxotrophs is only 40–50% of the magnitude in prototrophs. Furthermore, the auxotrophic cultures express autophagy genes at substantially lower levels, which likely contributes to their lower viability. Our observations suggest that a GR signal, which is a function of the abundance of essential natural nutrients, regulates fermentation/respiration, the GRR, and the CDC.

scholarly journals A conserved cell growth cycle can account for the environmental stress responses of divergent eukaryotes

2012 ◽  
Vol 23 (10) ◽  
pp. 1986-1997 ◽  
Author(s):  
Nikolai Slavov ◽  
Edoardo M. Airoldi ◽  
Alexander van Oudenaarden ◽  
David Botstein
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Oxygen Consumption ◽  
Heat Stress ◽  
Cell Division ◽  
Environmental Stress ◽  
Fission Yeast ◽  
Budding Yeast ◽  
Cell Division Cycle ◽  
Metabolic Cycle

The respiratory metabolic cycle in budding yeast (Saccharomyces cerevisiae) consists of two phases that are most simply defined phenomenologically: low oxygen consumption (LOC) and high oxygen consumption (HOC). Each phase is associated with the periodic expression of thousands of genes, producing oscillating patterns of gene expression found in synchronized cultures and in single cells of slowly growing unsynchronized cultures. Systematic variation in the durations of the HOC and LOC phases can account quantitatively for well-studied transcriptional responses to growth rate differences. Here we show that a similar mechanism—transitions from the HOC phase to the LOC phase—can account for much of the common environmental stress response (ESR) and for the cross-protection by a preliminary heat stress (or slow growth rate) to subsequent lethal heat stress. Similar to the budding yeast metabolic cycle, we suggest that a metabolic cycle, coupled in a similar way to the ESR, in the distantly related fission yeast, Schizosaccharomyces pombe, and in humans can explain gene expression and respiratory patterns observed in these eukaryotes. Although metabolic cycling is associated with the G0/G1 phase of the cell division cycle of slowly growing budding yeast, transcriptional cycling was detected in the G2 phase of the division cycle in fission yeast, consistent with the idea that respiratory metabolic cycling occurs during the phases of the cell division cycle associated with mass accumulation in these divergent eukaryotes.

scholarly journals Analysis of Gene Expression in Escherichia coli in Response to Changes of Growth-Limiting Nutrient in Chemostat Cultures

2004 ◽  
Vol 70 (4) ◽  
pp. 2354-2366 ◽  
Author(s):  
Qiang Hua ◽  
Chen Yang ◽  
Taku Oshima ◽  
Hirotada Mori ◽  
Kazuyuki Shimizu
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Growth Rate ◽  
Steady State ◽  
Specific Growth ◽  
Differentially Expressed ◽  
Transcriptional Responses ◽  
Chemostat Cultures ◽  
Limiting Nutrient ◽  
Slow Growing

ABSTRACT Studies of steady-state metabolic fluxes in Escherichia coli grown in nutrient-limited chemostat cultures suggest remarkable flux alterations in response to changes of growth-limiting nutrient in the medium (Hua et al., J. Bacteriol. 185:7053-7067, 2003). To elucidate the physiological adaptation of cells to the nutrient condition through the flux change and understand the molecular mechanisms underlying the change in the flux, information on gene expression is of great importance. DNA microarray analysis was performed to investigate the global transcriptional responses of steady-state cells grown in chemostat cultures with limited glucose or ammonia while other environmental conditions and the growth rate were kept constant. In slow-growing cells (specific growth rate of 0.10 h−1), 9.8% of a total of 4,071 genes investigated, especially those involved in amino acid metabolism, central carbon and energy metabolism, transport system and cell envelope, were observed to be differentially expressed between the two nutrient-limited cultures. One important characteristic of E. coli grown under nutrient limitation was its capacity to scavenge carbon or nitrogen from the medium through elevating the expression of the corresponding transport and assimilation genes. The number of differentially expressed genes in faster-growing cells (specific growth rate of 0.55 h−1), however, decreased to below half of that in slow-growing cells, which could be explained by diverse transcriptional responses to the growth rate under different nutrient limitations. Independent of the growth rate, 92 genes were identified as being differentially expressed. Genes tightly related to the culture conditions were highlighted, some of which may be used to characterize nutrient-limited growth.

Modulation of first-passage time for gene expression via asymmetric cell division

2019 ◽  
Vol 12 (05) ◽  
pp. 1950052
Author(s):  
Kunwen Wen ◽  
Lifang Huang ◽  
Qi Wang ◽  
Jianshe Yu
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Cell Division ◽  
Asymmetric Cell Division ◽  
First Passage Time ◽  
Passage Time ◽  
Exponential Growth Rate ◽  
First Passage ◽  
Division Rate ◽  
The Mean

How to balance the size of exponentially growing cells has always been a focus of biologists. Recent experiments have uncovered that the cell is divided into two daughter cells only when the level of time-keeper protein reaches a fixed threshold and cell division in prokaryote is not completely symmetric. The timing of cell division is essentially random because gene expression is stochastic, but cells seen to manage to have precise timing of cell division events. Although the inter-cellular variability of gene expression has attracted much attention, the randomness of event timing has been rarely studied. In our analysis, the timing of cell division is formulated as the first-passage time (denoted by FPT) for time-keeper protein’s level to cross a critical threshold firstly, we derive exact analytical formulae for the mean and noise of FPT based on stochastic gene expression model with asymmetric cell division. The results of numerical simulation show that the regulatory factors (division rate, newborn cell size, exponential growth rate and threshold) have significant influence on the mean and noise of FPT. We also show that both the increase of division rate and newborn cell size could reduce the mean of FPT and increase the noise of FPT, the larger the exponential growth rate is, the smaller the mean and noise of FPT will be; and the larger the threshold value is, the higher the mean of FPT is and the lower the noise is. In addition, compared with symmetric division, asymmetric division can reduce the mean of FPT and improve the noise of FPT. In summary, our results provide insight into the relationship between regulatory factors and FPT and reveal that asymmetric division is an effective mechanism to shorten the mean of FPT.

scholarly journals Cycles of gene expression and genome response during mammalian tissue regeneration

2018 ◽  
Author(s):  
Leonor Rib ◽  
Dominic Villeneuve ◽  
Viviane Praz ◽  
Nouria Hernandez ◽  
Nicolas Guex ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Division ◽  
De Novo ◽  
Cell Division Cycle ◽  
Transcriptional Responses ◽  
Mrna Accumulation ◽  
Gene Expression Response ◽  
Pol Ii ◽  
Sham Surgery ◽  
Internal Exon

AbstractBackgroundCompensatory liver hyperplasia — or regeneration — induced by two-thirds partial hepatectomy (PH) permits the study of synchronized activation of mammalian gene expression, particularly in relation to cell proliferation. Here, we measured genomic transcriptional responses and mRNA accumulation changes after PH and sham surgeries.ResultsDuring the first 10–20 hours, the PH- and sham-surgery responses were very similar, including parallel early activation of cell-division-cycle genes. After 20 hours, however, whereas post-PH livers continued with a robust and coordinate cell-division-cycle gene-expression response before returning to the resting state by one week, sham-surgery livers returned directly to a resting gene-expression state. Localization of RNA polymerase II (Pol II), and trimethylated histone H3 lysine 4 (H3K4me3) and 36 (H3K36me3) on genes dormant in the resting liver and activated during the PH response revealed a general de novo promoter Pol II recruitment and H3K4me3 increase during the early 10–20 hour phase followed by Pol II elongation and H3K36me3 accumulation in gene bodies during the later proliferation phase. H3K36me3, generally appearing at the first-internal exon, was preceded 5′ by H3K36me2; 3′ of the first-internal exon, in about half of genes H3K36me3 predominated and in the other half H3K36me2 and H3K36me3 co-existed. Further, we observed some unusual gene profiles with abundant Pol II but little evident H3K4me3 or H3K36me3 modification, indicating that these modifications are neither universal nor essential partners to Pol II transcription.ConclusionsPH and sham surgical procedures on mice reveal striking early post-operatory gene expression similarities followed by synchronized mRNA accumulation and epigenetic histone mark changes specific to PH.

Gastrin regulates growth of human pancreatic cancer in a tonic and autocrine fashion

1996 ◽  
Vol 270 (5) ◽  
pp. R1078-R1084 ◽  
Author(s):  
J. P. Smith ◽  
A. Shih ◽  
Y. Wu ◽  
P. J. McLaughlin ◽  
I. S. Zagon
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Pancreatic Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Pancreatic Cancer ◽  
Growth Media ◽  
Human Pancreatic Cancer Cell ◽  
Cell Extracts

The gastrointestinal peptides gastrin and cholecystokinin (CCK) stimulate growth of human pancreatic cancer through a CCK-B/gastrin- like receptor. In the present study we evaluated whether growth of human pancreatic cancer is endogenously regulated by gastrin. Immunohistomical examination of BxPC-3 cells and tumor xenografts revealed specifc gastrin immunoreactivity. Gastrin was detected by radioimmunoassay in pancreatic cancer cell extracts and in pancreatic cancer cell extracts and in the growth media. With use of reverse-transcriptase polymerase chain reaction gastrin gene expression was detected in both cultured BxPC-3 cancer cells and transplanted tumors, as well as seven addition human pancreatic cancer cell lines. Growth of BxPC-3 human pancreatic cancer cell in serum-free medium was inhibited by the addition of the CCK-B/gastrin receptor antagonist L-365,260, and gastrin treatment reversed the inhibitory effect of the antagonist. A selective gastrin antibody (Ab repressed growth of BxPC-3 cells. Gastrin immunoreactivity was detected in fresh human pancreatic cancer specimens but not in normal human pancreatic tissue. These data provide the first evidence that growth of a human pancreatic cancer is tonically stimulated by the autocrine production of gastrin. Evidence for the ubiquity of this system was provided by the detection of gastrin gene expression in multiple human pancreatic cancer cell lines and detection of gastrin in cell lines and fresh pancreatic tumors.

scholarly journals Coactivator PC4 Mediates AP-2 Transcriptional Activity and Suppresses ras-Induced Transformation Dependent on AP-2 Transcriptional Interference

1999 ◽  
Vol 19 (1) ◽  
pp. 899-908 ◽  
Author(s):  
Perry Kannan ◽  
Michael A. Tainsky
Keyword(s):  
Gene Expression ◽  
Growth Rate ◽  
Transcription Factors ◽  
Cell Lines ◽  
Transcriptional Activity ◽  
Suppressive Effect ◽  
Transcriptional Coactivator ◽  
Transcriptional Interference ◽  
Mechanism Of Inhibition ◽  
Teratocarcinoma Cells

ABSTRACT ras oncogene-transformed PA-1 human teratocarcinoma cells have abundant AP-2 mRNA but, paradoxically, little AP-2 transcriptional activity. We have previously shown that overexpression of AP-2 in nontumorigenic variants of PA-1 cells results in inhibition of AP-2 activity and induction of tumorigenicity similar to that caused by ras transformation of PA-1 cells. Evidence indicated the existence of a novel mechanism of inhibition of AP-2 activity involving sequestering of transcriptional coactivators. In this study, we found that PC4 is a positive coactivator of AP-2 and can restore AP-2 activity in ras-transformed PA-1 cells. Relative to vector-transfected ras cell lines,ras cell lines stably transfected with and expressing the PC4 cDNA have a diminished growth rate and exhibit a loss of anchorage-independent growth, and they are unable to induce the formation of tumors in nude mice. These data suggest that a transcriptional coactivator, like a tumor suppressor, can have a growth-suppressive effect on cells. Our experiments are the first to show that ras oncogenes and oncogenic transcription factors can induce transformation through effects on the transcription machinery rather than through specific programs of gene expression.

scholarly journals Transcriptional analysis of the response of C. elegans to ethanol exposure

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mark G. Sterken ◽  
Marijke H. van Wijk ◽  
Elizabeth C. Quamme ◽  
Joost A. G. Riksen ◽  
Lucinda Carnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Physiological Response ◽  
Physiological Responses ◽  
Ethanol Exposure ◽  
Transcriptional Analysis ◽  
Transcriptional Responses ◽  
Genetic Pathways ◽  
C Elegans ◽  
Chronic Ethanol Consumption ◽  
Transcriptional Changes

AbstractEthanol-induced transcriptional changes underlie important physiological responses to ethanol that are likely to contribute to the addictive properties of the drug. We examined the transcriptional responses of Caenorhabditis elegans across a timecourse of ethanol exposure, between 30 min and 8 h, to determine what genes and genetic pathways are regulated in response to ethanol in this model. We found that short exposures to ethanol (up to 2 h) induced expression of metabolic enzymes involved in metabolizing ethanol and retinol, while longer exposure (8 h) had much more profound effects on the transcriptome. Several genes that are known to be involved in the physiological response to ethanol, including direct ethanol targets, were regulated at 8 h of exposure. This longer exposure to ethanol also resulted in the regulation of genes involved in cilia function, which is consistent with an important role for the effects of ethanol on cilia in the deleterious effects of chronic ethanol consumption in humans. Finally, we found that food deprivation for an 8-h period induced gene expression changes that were somewhat ameliorated by the presence of ethanol, supporting previous observations that worms can use ethanol as a calorie source.

scholarly journals Individual Matrix Metalloproteinases Control Distinct Transcriptional Responses in Airway Epithelial Cells Infected with Pseudomonas aeruginosa

2007 ◽  
Vol 75 (12) ◽  
pp. 5640-5650 ◽  
Author(s):  
Sean Y. Kassim ◽  
Sina A. Gharib ◽  
Brigham H. Mecham ◽  
Timothy P. Birkland ◽  
William C. Parks ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pseudomonas Aeruginosa ◽  
Initial Point ◽  
Global Gene Expression ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Transcriptional Responses ◽  
Matrix Metalloproteinase 7 ◽  
Node Network ◽  
Global Gene Expression Analysis

ABSTRACT Airway epithelium is the initial point of host-pathogen interaction in Pseudomonas aeruginosa infection, an important pathogen in cystic fibrosis and nosocomial pneumonia. We used global gene expression analysis to determine airway epithelial transcriptional responses dependent on matrilysin (matrix metalloproteinase 7 [MMP-7]) and stromelysin-2 (MMP-10), two MMPs induced by acute P. aeruginosa pulmonary infection. Extraction of differential gene expression (EDGE) analysis of gene expression changes in P. aeruginosa-infected organotypic tracheal epithelial cell cultures from wild-type, Mmp7 −/−, and Mmp10 −/− mice identified 2,091 matrilysin-dependent and 1,628 stromelysin-2-dependent genes that were differentially expressed. Key node network analysis showed that these MMPs controlled distinct gene expression programs involved in proliferation, cell death, immune responses, and signal transduction, among other host defense processes. Our results demonstrate discrete roles for these MMPs in regulating epithelial responses to Pseudomonas infection and show that a global genomics strategy can be used to assess MMP function.

scholarly journals Growth Media Induces Variation in Cell Wall Associated Gene Expression in Arabidopsis thaliana Pollen Tube

Plants ◽  
2013 ◽  
Vol 2 (3) ◽  
pp. 429-440 ◽  
Author(s):  
Mário da Costa ◽  
Luís Pereira ◽  
Sílvia Coimbra
Keyword(s):  
Gene Expression ◽  
Arabidopsis Thaliana ◽  
Cell Wall ◽  
Pollen Tube ◽  
Growth Media

scholarly journals Quantitative Interaction Effects of Carbon Dioxide, Sodium Chloride, and Sodium Nitrite on Neurotoxin Gene Expression in Nonproteolytic Clostridium botulinum Type B

2004 ◽  
Vol 70 (5) ◽  
pp. 2928-2934 ◽  
Author(s):  
Maria Lövenklev ◽  
Ingrid Artin ◽  
Oskar Hagberg ◽  
Elisabeth Borch ◽  
Elisabet Holst ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Dioxide ◽  
Growth Rate ◽  
Sodium Chloride ◽  
Optical Density ◽  
Sodium Nitrite ◽  
Clostridium Botulinum ◽  
Lag Phase ◽  
Type B ◽  
Phase Duration

ABSTRACT The effects of carbon dioxide, sodium chloride, and sodium nitrite on type B botulinum neurotoxin (BoNT/B) gene (cntB) expression in nonproteolytic Clostridium botulinum were investigated in a tryptone-peptone-yeast extract (TPY) medium. Various concentrations of these selected food preservatives were studied by using a complete factorial design in order to quantitatively study interaction effects, as well as main effects, on the following responses: lag phase duration (LPD), growth rate, relative cntB expression, and extracellular BoNT/B production. Multiple linear regression was used to set up six statistical models to quantify and predict these responses. All combinations of NaCl and NaNO2 in the growth medium resulted in a prolonged lag phase duration and in a reduction in the specific growth rate. In contrast, the relative BoNT/B gene expression was unchanged, as determined by the cntB-specific quantitative reverse transcription-PCR method. This was confirmed when we measured the extracellular BoNT/B concentration by an enzyme-linked immunosorbent assay. CO2 was found to have a major effect on gene expression when the cntB mRNA levels were monitored in the mid-exponential, late exponential, and late stationary growth phases. The expression of cntB relative to the expression of the 16S rRNA gene was stimulated by an elevated CO2 concentration; the cntB mRNA level was fivefold greater in a 70% CO2 atmosphere than in a 10% CO2 atmosphere. These findings were also confirmed when we analyzed the extracellular BoNT/B concentration; we found that the concentrations were 27 ng · ml−1 · unit of optical density−1 in the 10% CO2 atmosphere and 126 ng · ml−1 · unit of optical density−1 in the 70% CO2 atmosphere.

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