Stochastic epigenetic dynamics of gene switching

The fusion of human fetal erythroid (HFE) cells with mouse erythroleukemia (MEL) cells produces stable synkaryons (HFE x MEL) which can be monitored for extended periods of time in culture. Initially these hybrids express a human fetal globin program (gamma >> beta), but after weeks or months in culture, they switch to an adult pattern of globin expression (beta >> gamma). The rate at which hybrids switch to the adult phenotype is roughly dependent on the gestational age of the fetal erythroid cells used in the fusion, suggesting that the rate of switching in vitro may be determined by a developmental clock type of mechanism, possibly involving the cumulative number of divisions experienced by the human fetal cells. To investigate whether the number or rate of cell divisions postfusion can influence the rate of switching, we monitored the rate of switching in hybrids from independent fusions under growth-promoting (serum-replete) and growth-suppressing (serum-deprived) conditions. We found that hybrids grown under serum-deprived or serumless conditions switched more rapidly to adult globin expression than did their counterparts in serum-replete conditions. Neither the number of cumulative cell divisions nor time in culture per se predicted the rate of switching in vitro. Our data suggest that factors present in serum either retard switching of hybrids by their presence or promote switching by their absence, indicating that globin switching in vitro can be modulated by the environment; however, once switching in HFE x MEL hybrids is complete, serum factors cannot reverse this process.

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Bi-directional gene switching with the tetracycline repressor and a novel tetracycline antagonist

Nucleic Acids Research ◽

10.1093/nar/24.15.2900 ◽

1996 ◽

Vol 24 (15) ◽

pp. 2900-2904 ◽

Cited By ~ 20

Author(s):

J Chrast-Balz

Keyword(s):

Gene Switching ◽

Tetracycline Repressor

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Feedback-Induced Variations of Distribution in a Representative Gene Model

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127415400088 ◽

2015 ◽

Vol 25 (07) ◽

pp. 1540008

Author(s):

Peijiang Liu ◽

Zhanjiang Yuan ◽

Lifang Huang ◽

Tianshou Zhou

Keyword(s):

Gene Expression ◽

Power Law ◽

Positive Feedback ◽

Bimodal Distribution ◽

Stochastic Bifurcation ◽

Protein Distribution ◽

Identical Cell ◽

Induced Changes ◽

Gene Switching ◽

Cell To Cell Variability

Gene expression is inherently noisy, implying that the number of mRNAs or proteins is not invariant rather than follows a distribution. This distribution can not only provide the exact information on the dynamics of gene expression but also describe cell-to-cell variability in a genetically identical cell population. Here, we systematically investigate a two-state model of gene expression, a model paradigm used to study expression dynamics, focusing on the effect of feedback on the type of mRNA or protein distribution. If there is no feedback, then the distribution may be bimodal, power-law tailed, or Poisson-like, depending on gene switching rates. However, we find that feedback can tune or change the type of the distribution in each case and tends to unimodalize the distribution as its strength increases. Specifically, positive feedback can change not only a power-law tailed distribution into a bimodal or Poisson-like distribution but also a bimodal distribution into a Poisson-like distribution (implying that stochastic bifurcation can take place). In addition, it can make a Poisson-like distribution become more peaked but does not change the type of this distribution. In contrast to positive feedback, negative feedback has less influence on the shape of the distributions except for the bimodal case. In all cases, the noise-feedback curve used extensively in previous studies cannot well reflect the feedback-induced changes in the shape of distributions. Feedback-induced variations in distribution would be important for cell survival in fluctuating environments.

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Developmental regulation of β-globin gene switching

Cell ◽

10.1016/0092-8674(88)90005-0 ◽

1988 ◽

Vol 55 (1) ◽

pp. 17-26 ◽

Cited By ~ 157

Author(s):

Ok-Ryun Baik Choi ◽

James Douglas Engel

Keyword(s):

Developmental Regulation ◽

Globin Gene ◽

Gene Switching

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Mating-type Gene Switching in Saccharomyces cerevisiae

Mobile DNA III ◽

10.1128/9781555819217.ch23 ◽

2015 ◽

pp. 491-514

Author(s):

Cheng-Sheng Lee ◽

James E. Haber

Keyword(s):

Saccharomyces Cerevisiae ◽

Mating Type ◽

Mating Type Gene ◽

Type Gene ◽

Gene Switching

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Intravenous Delivery of piggyBac Transposons as a Useful Tool for Liver-Specific Gene-Switching

International Journal of Molecular Sciences ◽

10.3390/ijms19113452 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3452 ◽

Cited By ~ 9

Author(s):

Shingo Nakamura ◽

Masayuki Ishihara ◽

Satoshi Watanabe ◽

Naoko Ando ◽

Masato Ohtsuka ◽

...

Keyword(s):

Plasmid Dna ◽

Chain Gene ◽

Specific Gene ◽

Chromosomal Integration ◽

Hepatic Disorder ◽

Murine Liver ◽

A Chain ◽

Gene Switching

Hydrodynamics-based gene delivery (HGD) is an efficient method for transfecting plasmid DNA into hepatocytes in vivo. However, the resulting gene expression is transient, and occurs in a non-tissue specific manner. The piggyBac (PB) transposon system allows chromosomal integration of a transgene in vitro. This study aimed to achieve long-term in vivo expression of a transgene by performing hepatocyte-specific chromosomal integration of the transgene using PB and HGD. Using this approach, we generated a novel mouse model for a hepatic disorder. A distinct signal from the reporter plasmid DNA was discernible in the murine liver approximately two months after the administration of PB transposons carrying a reporter gene. Then, to induce the hepatic disorder, we first administered mice with a PB transposon carrying a CETD unit (loxP-flanked stop cassette, diphtheria toxin-A chain gene, and poly(A) sites), and then with a plasmid expressing the Cre recombinase under the control of a liver-specific promoter. We showed that this system can be used for in situ manipulation and analysis of hepatocyte function in vivo in non-transgenic (Tg) animals.

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Analysis of stochastic timing of intracellular events with gene switching

10.1101/710442 ◽

2019 ◽

Author(s):

Khem Raj Ghusinga ◽

Abhyudai Singh

Keyword(s):

First Passage Time ◽

Regulatory Protein ◽

Gene Activation ◽

Threshold Level ◽

Passage Time ◽

First Passage ◽

Cellular Processes ◽

Event Timing ◽

Activation Rates ◽

Gene Switching

AbstractAn important step in execution of several cellular processes is accumulation of a regulatory protein up to a specific threshold level. Since production of a protein is inherently stochastic, the time at which its level crosses a threshold exhibits cell-to-cell variation. A problem of interest is to characterize how the statistics of event timing is affected by various steps of protein expression. Our previous work studied this problem by considering a gene expression model where gene was always active. Here we extend our analysis to a scenario where gene stochastically switches between active and inactive states. We formulate event timing as the first-passage time for a protein’s level to cross a threshold and investigate how the rates of gene activation/inactivation affect the distribution and moments of the first-passage time. Our results show that both the time-scale of gene switching with respect to the protein degradation rate as well as the ratio of the gene inactivation to gene activation rates are important parameters in shaping the event-timing distribution.

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Synergistic regulation of human beta-globin gene switching by locus control region elements HS3 and HS4.

Genes & Development ◽

10.1101/gad.9.24.3083 ◽

1995 ◽

Vol 9 (24) ◽

pp. 3083-3096 ◽

Cited By ~ 142

Author(s):

J Bungert ◽

U Dave ◽

K C Lim ◽

K H Lieuw ◽

J A Shavit ◽

...

Keyword(s):

Control Region ◽

Globin Gene ◽

Locus Control Region ◽

Beta Globin ◽

Beta Globin Gene ◽

Synergistic Regulation ◽

Gene Switching

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The Plasmodium falciparum var gene switching rate, switching mechanism and patterns of parasite recrudescence described by mathematical modelling

Parasitology ◽

10.1017/s0031182001001160 ◽

2002 ◽

Vol 124 (3) ◽

pp. 225-235 ◽

Cited By ~ 43

Author(s):

S. PAGET-MCNICOL ◽

M. GATTON ◽

I. HASTINGS ◽

A. SAUL

Keyword(s):

Plasmodium Falciparum ◽

Chronic Infection ◽

Malaria Parasite ◽

Gene Repertoire ◽

Switching Rate ◽

Specific Immunity ◽

Parasite Survival ◽

Gene Switching ◽

Variant Antigen ◽

Var Gene

Recrudescing Plasmodium falciparum parasitaemia is attributed to the switching of PfEMP1, a variant antigen family encoded by the var gene repertoire, and the host's immune response. We have developed a mathematical model which incorporates var gene switching, and variant specific, non-variant specific and non-specific immunity. By conducting a sensitivity analysis of the model we have defined the parameter limits which produce chronic and recrudescing infections. We explore 3 switching mechanisms: ordered, random and uncoupled switching. We show that if var genes switch on and off independently at variable rates through the repertoire a chronic clinical infection is predicted. The fastest switching-on rate that produces a chronic infection is 0·03% per generation. The model predicts that non-variant specific immunity plays an important role in reducing disease severity. This work illustrates the complex relationship between the malaria parasite and its host and shows that var gene switching at rates substantially slower than 2% are essential for parasite survival.

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