Analytical time-dependent distributions for gene expression models with complex promoter switching mechanisms

Mapping Intimacies ◽

10.1101/2022.01.05.475050 ◽

2022 ◽

Author(s):

Chen Jia ◽

Youming Li

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

Switching Time ◽

Time Dependent ◽

Molecular Memory ◽

Dynamical Phase ◽

Copy Numbers ◽

Multiple Promoter ◽

Analytical Time ◽

Appl Math

Classical gene expression models assume exponential switching time distributions between the active and inactive promoter states. However, recent experiments have shown that many genes in mammalian cells may produce non-exponential switching time distributions, implying the existence of multiple promoter states and molecular memory in the promoter switching dynamics. Here we analytically solve a gene expression model with random bursting and complex promoter switching, and derive the time-dependent distributions of the mRNA and protein copy numbers, generalizing the steady-state solutions obtained in [SIAM J. Appl. Math. 72, 789-818 (2012)] and [SIAM J. Appl. Math. 79, 1007-1029 (2019)]. Using multiscale simplification techniques, we find that molecular memory has no influence on the time-dependent distribution when promoter switching is very fast or very slow, while it significantly affects the distribution when promoter switching is neither too fast nor too slow. By analyzing the dynamical phase diagram of the system, we also find that molecular memory in the inactive gene state weakens the transient and stationary bimodality of the copy number distribution, while molecular memory in the active gene state enhances such bimodality.

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A synthetic circuit for buffering gene dosage variation between individual mammalian cells

Nature Communications ◽

10.1038/s41467-021-23889-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jin Yang ◽

Jihwan Lee ◽

Michelle A. Land ◽

Shujuan Lai ◽

Oleg A. Igoshin ◽

...

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

Feedforward Control ◽

Gene Dosage ◽

Wide Distribution ◽

Biological Research ◽

Plasmid Copy ◽

Control Of Gene Expression ◽

Copy Numbers ◽

Wide Range

AbstractPrecise control of gene expression is critical for biological research and biotechnology. However, transient plasmid transfections in mammalian cells produce a wide distribution of copy numbers per cell, and consequently, high expression heterogeneity. Here, we report plasmid-based synthetic circuits – Equalizers – that buffer copy-number variation at the single-cell level. Equalizers couple a transcriptional negative feedback loop with post-transcriptional incoherent feedforward control. Computational modeling suggests that the combination of these two topologies enables Equalizers to operate over a wide range of plasmid copy numbers. We demonstrate experimentally that Equalizers outperform other gene dosage compensation topologies and produce as low cell-to-cell variation as chromosomally integrated genes. We also show that episome-encoded Equalizers enable the rapid generation of extrachromosomal cell lines with stable and uniform expression. Overall, Equalizers are simple and versatile devices for homogeneous gene expression and can facilitate the engineering of synthetic circuits that function reliably in every cell.

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Dynamic Changes in the Regulation of Energy Balance after Roux-en-Y Gastric Bypass Are Reflected in Time-Dependent Alterations in Liver Gene Expression

Diabetes ◽

10.2337/db18-289-lb ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 289-LB

Author(s):

M. AGOSTINA SANTORO ◽

JOSEPH BRANCALE ◽

JILL CARMODY GARRISON ◽

SRIRAM MACHINENI ◽

SCOTT A. LAJOIE ◽

...

Keyword(s):

Gene Expression ◽

Gastric Bypass ◽

Energy Balance ◽

Time Dependent ◽

Dynamic Changes ◽

Liver Gene

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Faculty Opinions recommendation of Stable suppression of gene expression by RNAi in mammalian cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1003878.51162 ◽

2002 ◽

Author(s):

Ashok Venkitaraman

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

Suppression Of Gene Expression

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Moxifloxacin Activates the SOS Response in Mycobacterium tuberculosis in a Dose- and Time-Dependent Manner

Microorganisms ◽

10.3390/microorganisms9020255 ◽

2021 ◽

Vol 9 (2) ◽

pp. 255

Author(s):

Angelo Iacobino ◽

Giovanni Piccaro ◽

Manuela Pardini ◽

Lanfranco Fattorini ◽

Federico Giannoni

Keyword(s):

Gene Expression ◽

Mycobacterium Tuberculosis ◽

Physiological State ◽

Transcriptional Response ◽

Sos Response ◽

Resistant Mutant ◽

Time Dependent ◽

Dependent Manner ◽

Gyra Gene ◽

Drug Concentrations

Previous studies on Escherichia coli demonstrated that sub-minimum inhibitory concentration (MIC) of fluoroquinolones induced the SOS response, increasing drug tolerance. We characterized the transcriptional response to moxifloxacin in Mycobacterium tuberculosis. Reference strain H37Rv was treated with moxifloxacin and gene expression studied by qRT-PCR. Five SOS regulon genes, recA, lexA, dnaE2, Rv3074 and Rv3776, were induced in a dose- and time-dependent manner. A range of moxifloxacin concentrations induced recA, with a peak observed at 2 × MIC (0.25 μg/mL) after 16 h. Another seven SOS responses and three DNA repair genes were significantly induced by moxifloxacin. Induction of recA by moxifloxacin was higher in log-phase than in early- and stationary-phase cells, and absent in dormant bacilli. Furthermore, in an H37Rv fluoroquinolone-resistant mutant carrying the D94G mutation in the gyrA gene, the SOS response was induced at drug concentrations higher than the mutant MIC value. The 2 × MIC of moxifloxacin determined no significant changes in gene expression in a panel of 32 genes, except for up-regulation of the relK toxin and of Rv3290c and Rv2517c, two persistence-related genes. Overall, our data show that activation of the SOS response by moxifloxacin, a likely link to increased mutation rate and persister formation, is time, dose, physiological state and, possibly, MIC dependent.

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The Sex Differences in Uveal Melanoma: Potential Roles of EIF1AX, Immune Response and Redox Regulation

Current Oncology ◽

10.3390/curroncol28040245 ◽

2021 ◽

Vol 28 (4) ◽

pp. 2801-2811

Author(s):

Feng Liu-Smith ◽

Chi-Yang Chiu ◽

Daniel L. Johnson ◽

Phillip Winston Miller ◽

Evan S. Glazer ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

Sex Difference ◽

Uveal Melanoma ◽

Disulfide Bond ◽

Bond Formation ◽

Disulfide Bond Formation ◽

Men And Women ◽

Copy Numbers ◽

Differential Gene

Background: Uveal melanoma (UVM) is a rare cancer that shows sex difference in incidence and survival, with little previous report for the underlying mechanism. Methods: This study used the SEER data (1974–2016) for an age-dependent analysis on sex difference in UVM, and further used the TCGA-UVM genomics dataset for analyzing the differential gene expression profiles in tumors from men and women. Results: Our results demonstrate a sex difference in older age (≥40 years) but not in younger patients, with men exhibiting a higher incidence rate than women. However, younger women have shown a continuous increasing trend since 1974. Examining the 11 major oncogenes and tumor suppressors in UVM revealed that EIF1AX showed a significant sex difference in mRNA accumulation and copy number variation, with female tumors expressing higher levels of EIF1AX and exhibiting more variations in copy numbers. EIF1AX mRNA levels were significantly inversely correlated with EIF1AX copy numbers in female tumors only, but not in male tumors. Differential gene expression analysis at the whole genomic level identified a set of 92 protein-coding and 16 RNA-coding genes which exhibited differential expression in men and women (fold of change cutoff at 1.7, adjusted p value < 0.05, FDR < 0.05). Network analysis showed significant difference in immune response and in disulfide bond formation, with EGR1/EGR2 and PDIA2 genes as regulators for immune response and disulfide bond formation, respectively. The melanocortin pathway which is linked to both melanin synthesis and obesity seems to be altered with unclear significance, as the sex difference in POMC, DCT/TYRP2, and MRAP2 was observed but with no clear direction. Conclusion: This study reveals possible mechanisms for the sex difference in tumorigenesis of UVM which has potentials for better understanding and prevention of UVM.

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High-performance chemical- and light-inducible recombinases in mammalian cells and mice

Nature Communications ◽

10.1038/s41467-019-12800-7 ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 9

Author(s):

Benjamin H. Weinberg ◽

Jang Hwan Cho ◽

Yash Agarwal ◽

N. T. Hang Pham ◽

Leidy D. Caraballo ◽

...

Keyword(s):

Gene Expression ◽

Mammalian Cells ◽

High Performance ◽

Genome Engineering ◽

Genetic Circuits ◽

Control Of Gene Expression ◽

Expression Control ◽

Gene Expression Control ◽

High Performance Systems ◽

Spatiotemporal Control

Abstract Site-specific DNA recombinases are important genome engineering tools. Chemical- and light-inducible recombinases, in particular, enable spatiotemporal control of gene expression. However, inducible recombinases are scarce due to the challenge of engineering high performance systems, thus constraining the sophistication of genetic circuits and animal models that can be created. Here we present a library of >20 orthogonal inducible split recombinases that can be activated by small molecules, light and temperature in mammalian cells and mice. Furthermore, we engineer inducible split Cre systems with better performance than existing systems. Using our orthogonal inducible recombinases, we create a genetic switchboard that can independently regulate the expression of 3 different cytokines in the same cell, a tripartite inducible Flp, and a 4-input AND gate. We quantitatively characterize the inducible recombinases for benchmarking their performances, including computation of distinguishability of outputs. This library expands capabilities for multiplexed mammalian gene expression control.

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Time Dependent Gene Expression Changes in the Liver of Mice Treated with Benzene

Biomarker Insights ◽

10.4137/bmi.s590 ◽

2008 ◽

Vol 3 ◽

pp. BMI.S590 ◽

Cited By ~ 3

Author(s):

Han-Jin Park ◽

Jung Hwa Oh ◽

Seokjoo Yoon ◽

S.V.S. Rana

Keyword(s):

Gene Expression ◽

Expression Profiles ◽

Gene Expression Profiles ◽

General Purpose ◽

Time Dependent ◽

Expression Data ◽

Benzene Exposure ◽

Microarray Analyses ◽

First Time ◽

Affymetrix Gene Chip

Benzene is used as a general purpose solvent. Benzene metabolism starts from phenol and ends with p-benzoquinone and o-benzoquinone. Liver injury inducted by benzene still remains a toxicologic problem. Tumor related genes and immune responsive genes have been studied in patients suffering from benzene exposure. However, gene expression profiles and pathways related to its hepatotoxicity are not known. This study reports the results obtained in the liver of BALB/C mice (SLC, Inc., Japan) administered 0.05 ml/100 g body weight of 2% benzene for six days. Serum, ALT, AST and ALP were determined using automated analyzer (Fuji., Japan). Histopathological observations were made to support gene expression data. c-DNA microarray analyses were performed using Affymetrix Gene-chip system. After six days of benzene exposure, twenty five genes were down regulated whereas nineteen genes were up-regulated. These gene expression changes were found to be related to pathways of biotransformation, detoxification, apoptosis, oxidative stress and cell cycle. It has been shown for the first time that genes corresponding to circadian rhythms are affected by benzene. Results suggest that gene expression profile might serve as potential biomarkers of hepatotoxicity during benzene exposure.

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