scholarly journals Stochastic steady state gain in a gene expression process with mRNA degradation control

2012 ◽  
Vol 9 (72) ◽  
pp. 1589-1598 ◽  
Author(s):  
Hiroyuki Kuwahara ◽  
Russell Schwartz
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Steady State ◽  
Protein Level ◽  
Mrna Level ◽  
System Level ◽  
Wide Range ◽  
Molecular Reactions ◽  
Transcriptional Bursting ◽  
Regulation Model

Recent analyses with high-resolution single-molecule experimental methods have shown highly irregular and variable bursting of mRNA in a wide range of organisms. Noise in gene expression is thought to be beneficial in cell fate specifications, as it can lay a foundation for phenotypic diversification of isogenetic cells in the homogeneous environment. However, because the stability of proteins is, in many cases, higher than that of mRNAs, noise from transcriptional bursting can be considerably buffered at the protein level, limiting the effect of noisy mRNAs at a more global regulation level. This raises a question as to what constructive role noisy mRNAs can play in the system-level dynamics. In this study, we have addressed this question using the computational models that extend the conventional transcriptional bursting model with a post-transcriptional regulation step. Surprisingly, by comparing this stochastic model with the corresponding deterministic model, we find that intrinsic fluctuations can substantially increase the expected mRNA level. Because effects of a higher mRNA level can be transmitted to the protein level even with slow protein degradation rates, this finding suggests that an increase in the protein level is another potential effect of transcriptional bursting. Here, we show that this striking steady state increase is caused by the asynchronous nature of molecular reactions, which allows the transcriptional regulation model to create additional modes of qualitatively distinct dynamics. Our results illustrate non-intuitive effects of reaction asynchronicity on system dynamics that cannot be captured by the traditional deterministic framework. Because molecular reactions are intrinsically stochastic and asynchronous, these findings may have broad implications in modelling and understanding complex biological systems.

scholarly journals Genotype-dependent and non-gradient patterns of RSV gene expression

2019 ◽  
Author(s):  
Felipe-Andrés Piedra ◽  
Xueting Qiu ◽  
Michael N. Teng ◽  
Vasanthi Avadhanula ◽  
Annette A. Machado ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Steady State ◽  
Transcription Initiation ◽  
Mrna Levels ◽  
Viral Pathogen ◽  
Negative Strand ◽  
Gene Start ◽  
Syncytial Virus ◽  
Conserved Gene

AbstractRespiratory syncytial virus (RSV) is a nonsegmented negative-strand (NNS) RNA virus and a leading cause of severe lower respiratory tract illness in infants and the elderly. Transcription of the ten RSV genes proceeds sequentially from the 3’ promoter and requires conserved gene start (GS) and gene end (GE) signals. Previous studies using the prototypical GA1 genotype Long and A2 strains have indicated a gradient of gene transcription. However, recent reports show data that appear inconsistent with a gradient. To better understand RSV transcriptional regulation, mRNA abundances from five RSV genes were measured by quantitative real-time PCR (qPCR) in three cell lines and cotton rats infected with virus isolates belonging to four different genotypes (GA1, ON, GB1, BA). Relative mRNA levels reached steady-state between four and 24 hours post-infection. Steady-state patterns were genotype-specific and non-gradient, where mRNA levels from the G (attachment) gene exceeded those from the more promoter-proximal N (nucleocapsid) gene across isolates. Transcript stabilities could not account for the non-gradient patterns observed, indicating that relative mRNA levels more strongly reflect transcription than decay. While the GS signal sequences were highly conserved, their alignment with N protein in the helical ribonucleocapsid, i.e., N-phase, was variable, suggesting polymerase recognition of GS signal conformation affects transcription initiation. The effect of GS N-phase on transcription efficiency was tested using dicistronic minigenomes. Ratios of minigenome gene expression showed a switch-like dependence on N-phase with a period of seven nucleotides. Our results indicate that RSV gene expression is in part sculpted by polymerases that initiate transcription with a probability dependent on GS signal N-phase.Author SummaryRSV is a major viral pathogen that causes significant morbidity and mortality, especially in young children. Shortly after RSV enters a host cell, transcription from its nonsegmented negative-strand (NNS) RNA genome starts at the 3’ promoter and proceeds sequentially. Transcriptional attenuation is thought to occur at each gene junction, resulting in a gradient of gene expression. However, recent studies showing non-gradient levels of RSV mRNA suggest that transcriptional regulation may have additional mechanisms. We show using RSV isolates belonging to four different genotypes that gene expression is genotype-dependent and one gene (the G or attachment gene) is consistently more highly expressed than an upstream neighbor. We hypothesize that variable alignment of highly conserved gene start (GS) signals with nucleoprotein (i.e., variable GS N-phase) can affect transcription and give rise to non-gradient patterns of gene expression. We show using dicistronic RSV minigenomes wherein the reporter genes differ only in the N-phase of one GS signal that GS N-phase affects gene expression. Our results suggest the existence of a novel mechanism of transcriptional regulation that might play a role in other NNS RNA viruses.

scholarly journals Differential regulation of γ-glutamylcysteine synthetase heavy and light subunit gene expression

1997 ◽  
Vol 326 (1) ◽  
pp. 167-172 ◽  
Author(s):  
Jiaxin CAI ◽  
Zong-Zhi HUANG ◽  
Shelly C. LU
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Steady State ◽  
Mrna Level ◽  
Rat Hepatocytes ◽  
Mrna Levels ◽  
Subunit Gene ◽  
Subunit Mrna ◽  
Glutamylcysteine Synthetase ◽  
Steady State Mrna Level

γ-Glutamylcysteine synthetase (GCS) is the rate-limiting enzyme in the biosynthesis of glutathione and is composed of a heavy and a light subunit. Although the heavy subunit is enzymically active alone, the light subunit plays an important regulatory role by making the holoenzyme function more efficiently. In the current study we examined whether conditions which are known to influence gene expression of the heavy subunit also influence that of the light subunit, and the mechanisms involved. Treatment of cultured rat hepatocytes with hormones such as insulin and hydrocortisone, or plating hepatocytes under low cell density increased the steady-state mRNA level of the heavy subunit only. Treatment with diethyl maleate (DEM), buthionine sulphoximine (BSO) and t-butylhydroquinone (TBH) increased the steady state mRNA level and gene transcription rates of both subunits. These treatments share in common their ability to induce oxidative stress and activate nuclear factor κB (NF-κB). Treatment with protease inhibitors 7-amino-1-chloro-3-tosylamido-2-heptanone (TLCK) or L-1-tosylamido-2-phenylethyl chloromethyl ketone (TPCK) had no influence on the basal NF-κB and GCS subunit mRNA levels, but blocked the activation of NF-κB by DEM, BSO and TBH, and the increase in GCS heavy subunit mRNA level by BSO and TBH. On the other hand, the DEM-, BSO- and TBH-induced increase in GCS light-subunit mRNA level was unaffected by TLCK and TPCK. Thus only the heavy subunit is hormonally regulated and growth sensitive, whereas both subunits are regulated by oxidative stress. Signalling through NF-κB is involved only in the oxidative-stress-mediated changes in the heavy subunit gene expression.

scholarly journals Multiple cytochrome P-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism

2011 ◽  
Vol 43 (1) ◽  
pp. 57-67 ◽  
Author(s):  
A. Catharine Ross ◽  
Christopher J. Cifelli ◽  
Reza Zolfaghari ◽  
Nan-qian Li
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Steady State ◽  
Vitamin A ◽  
Dynamic Range ◽  
Dynamic Change ◽  
The Body ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Wide Range

Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improvement of dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate, and supplemented) and acutely after administration of a therapeutic dose of all- trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P-450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P < 0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding retinoic acid receptor (RAR)β, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log 26 in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naive rats, evidenced by increased CYP26A1 gene expression and increased conversion of [3H]RA to polar metabolites. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling retinol-binding protein (RBP)4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.

scholarly journals Levels of G-proteins in liver and brain of lean and obese (ob/ob) mice

1992 ◽  
Vol 282 (1) ◽  
pp. 15-23 ◽  
Author(s):  
N McFarlane-Anderson ◽  
J Bailly ◽  
N Bégin-Heick
Keyword(s):  
Gene Expression ◽  
G Proteins ◽  
Protein Level ◽  
Mrna Level ◽  
Beta Subunits ◽  
Obese Mice ◽  
Protein Levels ◽  
Alpha Subunits ◽  
Brain Membranes ◽  
Liver Membranes

G-protein levels were assessed in liver and brain membranes of lean and obese mice. ADP-ribosylation and immunodetection studies revealed a decrease in the abundance of Gs and Gi alpha-subunits in the liver membranes of obese mice compared with lean mice. In contrast, in brain membranes, the abundance of these proteins was not significantly different between lean and obese mice. Studies at the mRNA level in both liver and brain revealed no difference in gene expression between lean and obese mice. Protein and mRNA studies both showed that Gs, Gi alpha 1, Gi alpha 2, Go alpha and G beta subunits are present in brain membranes, and Gi alpha 3 is barely detectable. In liver, Ga alpha, Gi alpha 2 and G beta subunits are the major constituents, whereas Gi alpha 1, Gi alpha 3 and Go alpha are barely detectable. It is possible that the differences observed at the protein level are due to different rates of translation of the mRNA. Different rates of release of the alpha-subunits from the membrane and/or different rates of degradation would also explain these results.

scholarly journals Novel Insights for PI3KC3 in Mediating Lipid Accumulation in Yellow Catfish Pelteobagrus Fulvidraco

2021 ◽  
Author(s):  
Mei-Qin Zhuo ◽  
Jun Chen ◽  
Mei-Li Wu ◽  
Wen-biao Wang
Keyword(s):  
Transcriptional Regulation ◽  
Protein Level ◽  
Lipid Accumulation ◽  
Mrna Level ◽  
Pelteobagrus Fulvidraco ◽  
Yellow Catfish ◽  
Site Mutation ◽  
Mobility Shift ◽  
Mobility Shift Assay ◽  
Mutation Assay

Abstract In this study, the transcriptional regulation of PI3KC3 by three transcript factors (PPARγ, PPARα and STAT3) and the potential role of PI3KC3 in mediating lipid accumulation were determined in yellow catfish Pelteobagrus fulvidraco. The 5’-deletion assay, overexpression assay, site-mutation assay and electrophoretic mobility shift assay suggested that PPARα, PPARγ and STAT3 negatively regulated the promoter activity of pi3kc3. Moreover, the transcriptional inactivation of pi3kc3 was directly mediated by PPARα and PPARγ under fatty acid (FA) treatment. Using primary hepatocytes from yellow catfish, FA incubation significantly increased triacylglyceride (TG), NEFA content, the mRNA level of pparα, pparγ, stat3 and dnmt3b, the protein level of PPARα, PPARγ and STAT3, and the methylation level of pi3kc3, but significantly reduced the mRNA and protein level of PI3KC3. Our findings offer new insights into the mechanisms for transcriptional regulation of PI3KC3 and for PI3KC3-mediated lipid accumulation in fish.

scholarly journals Decoding transcriptional regulation via a human gene expression predictor

2020 ◽  
Author(s):  
Yuzhou Wang ◽  
Yu Zhang ◽  
Jiazhen Gong ◽  
Jianqiang Bao ◽  
Shisong Ma
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Transcription Factors ◽  
Stress Response ◽  
Target Gene ◽  
Target Genes ◽  
Human Gene ◽  
Human Gene Expression ◽  
Novel Approach ◽  
Wide Range

ABSTRACTTranscription factors (TF) regulate cellular activities via controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes was lacking. We constructed a universal human gene expression predictor and utilized it to decode transcriptional regulation. Using 1613 TFs’ expression, the predictor reconstituted highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The predictor’s broad applicability indicated it had recapitulated the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs were then extracted from the predictor and enabled downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. Thus, we present a novel approach to study human transcriptional regulation following the “understanding by modeling” principle.

Complex transcriptional regulation of myc family gene expression in the developing mouse brain and liver

1991 ◽  
Vol 11 (12) ◽  
pp. 6007-6015
Author(s):  
L Xu ◽  
S D Morgenbesser ◽  
R A DePinho
Keyword(s):  
Gene Expression ◽  
Transcriptional Regulation ◽  
Steady State ◽  
High Rate ◽  
Developmental Expression ◽  
Tissue Type ◽  
Mrna Levels ◽  
Postnatal Brain ◽  
Transcriptional Initiation ◽  
Family Gene

myc family genes (c-, N-, and L-myc) have been shown to be differentially expressed with respect to tissue type and developmental stage. To define and compare the regulatory mechanisms governing their differential developmental expression, we examined the transcriptional regulation of each myc family member during murine postnatal brain and liver development. Nuclear run-on transcription assays demonstrated that both the rate of transcriptional initiation and the degree of transcriptional blocking contribute in a complex manner to the regulation of all three genes. During postnatal brain development, the relative contribution of each transcriptional control mechanism to the regulation of myc family gene expression was found to be different for each gene. For instance, while modulation of transcriptional attenuation did not appear to contribute to the down-regulation of L-myc expression, attenuation was found to be the dominant mechanism by which steady-state N-myc mRNA levels were down-regulated. Different transcriptional strategies were found to be employed in newborn versus adult developing liver for repression of N- and L-myc expression. Undetectable steady-state N- and L-myc mRNA levels in newborn liver were associated with a very low rate of transcriptional initiation, whereas the lack of N- and L-myc expression at the adult stage was accompanied by a high rate of initiation and a striking degree of transcriptional attenuation. Transcriptional attenuation in the N-myc gene was found to map to a region encoding a potential stem-loop structure followed by a thymine tract within the first exon and was not dependent on the use of a specific transcriptional start site.

Differential regulation of G protein expression in rat hearts exposed to chronic hypoxia

1995 ◽  
Vol 269 (6) ◽  
pp. H1865-H1873 ◽  
Author(s):  
R. Kacimi ◽  
J. M. Moalic ◽  
A. Aldashev ◽  
D. E. Vatner ◽  
J. P. Richalet ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Functional Activity ◽  
Protein Level ◽  
Chronic Hypoxia ◽  
Mrna Level ◽  
Mrna Levels ◽  
Protein Levels ◽  
Rat Hearts ◽  
And Function

Chronic hypoxia impairs adrenergic responsiveness. A modulation of Gs and/or G1 protein alpha-subunits may be associated with the downregulation of the beta-adrenergic receptors previously found in chronic hypoxia. G protein gene expression and protein level and function in rat hearts exposed to a 30-day hypobaric chronic hypoxia were compared with control rat hearts. No change was observed in G alpha s mRNA levels in either right or left ventricles. In right ventricles, mRNA levels of G alpha i-2 increased by 40% (P < 0.05), but not in left ventricles. In both left and right ventricles, chronic hypoxia did not modify G alpha i-2 and G alpha s protein amounts, but significantly decreased functional activity of G alpha s. In conclusion, gene expression, protein levels of G alpha s and G alpha i-2, and activity of G alpha s do not change in parallel fashion with chronic hypoxia. In chronic hypoxic right ventricles, although the mRNA level of G alpha i-2 is increased, the protein level is unchanged. One potential mechanism of desensitization to catecholamines in chronic hypoxia appears to involve a decreased functional activity of G alpha s in spite of normal mRNA and protein levels

The Respective Potential of Endurance Training on COUP-TF I and COUP-TF II Gene Expression in the Skeletal Muscle of Rats

2016 ◽  
Vol 13 (10) ◽  
pp. 6993-6998
Author(s):  
Haiyan Wang ◽  
Shuzhe Ding
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Blood Glucose ◽  
Endurance Training ◽  
Protein Level ◽  
Mrna Level ◽  
Control Group ◽  
Apparent Effect ◽  
Gk Rats ◽  
Sd Rats

Objective: The aim of this study was to investigate the effects of 6-week endurance training on COUP-TF I and COUP-TF II gene expression of SD rats and GK rats. Method: 20 male SD rats, about 4 weeks old, weighing 100 ± 5 g; 12 GK rats, about 8 weeks old, weighing 250 ± 5 g, SD rats were randomly divided into SD control group (C, n = 10), endurance group (E, n = 10), GK rats were randomly divided into GK control group (H, n = 6), endurance group (R, n = 6). Endurance training in rats for 6 weeks of treadmill training, training six days a week, once a day for a maximum speed of not more than 16.7 m/min, 1 hour a day. Real-time PCR was used to detect the mRNA level of COUP-TF I and COUP-TF II. Western Blotting was used to detect the protein level COUP-TF I. Results: (1) SD rats: endurance training significantly reduced blood glucose but had no apparent effect on IRI; endurance training significantly increased COUP-TF I mRNA level but significantly reduced COUP-TF II mRNA level; endurance exercises had no apparent effect on COUP-TF I protein level (2) GK rats: endurance training significantly reduced blood glucose and IRI; endurance training both significantly reduced the mRNA level of COUP-TF I and COUP-TF II; endurance training significantly reduced COUP-TF I protein level. Conclusion: (1) Endurance training was beneficial to reduce the level of blood glucose in GK rats, which may mitigate IR. (2) The effects of endurance exercise on COUP-TF I gene expression in skeletal muscle are opposite under normal physiological and diabetes, which may be related to the differences of strains, age and diet between GK rats and SD rats. (3) Compared with COUP-TF I, the adaptation of COUP-TF II mRNA level to endurance exercise was exactly the same for GK rats and SD rats, which indicating that the COUP-TF II mRNA level may play an important role in the effect of endurance training that can prevention and improvement of insulin resistance.

Sign in / Sign up

Export Citation Format

Share Document