scholarly journals Phase separation provides a mechanism to reduce noise in cells

2019 ◽  
Author(s):  
Florian Oltsch ◽  
Adam Klosin ◽  
Frank Julicher ◽  
Anthony A. Hyman ◽  
Christoph Zechner
Keyword(s):  
Gene Expression ◽  
Phase Separation ◽  
Mammalian Cells ◽  
Biological Information ◽  
Liquid Droplets ◽  
Gene Expression Noise ◽  
Noise In Gene Expression ◽  
Biological Information Processing ◽  
Cellular Control

A central problem in cellular control is how cells cope with the inherent noise in gene expression. Although transcriptional and posttranscriptional feedback mechanisms can suppress noise, they are often slow, and cannot explain how cells buffer acute fluctuations. Here, by using a physical model that links fluctuations in protein concentration to the theory of phase separation, we show that liquid droplets can act as fast and effective buffers for gene expression noise. We confirm our theory experimentally using an engineered phase separating protein that forms liquid-like compartments in mammalian cells. These data suggest a novel role of phase separation in biological information processing.

scholarly journals Paraspeckles: Paragons of functional aggregation

2015 ◽  
Vol 210 (4) ◽  
pp. 527-528 ◽  
Author(s):  
Edward Courchaine ◽  
Karla M. Neugebauer
Keyword(s):  
Gene Expression ◽  
Phase Separation ◽  
Low Complexity ◽  
Nuclear Body ◽  
Liquid Droplets ◽  
Cell Biol

Low-complexity proteins undergo phase separation in vitro, forming hydrogels or liquid droplets. Whether these form in vivo, and under what conditions, is still unclear. In this issue, Hennig et al. (2015. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201504117) show that formation of the paraspeckle, a nuclear body that regulates gene expression, requires low-complexity prion-like domains (PLDs) within paraspeckle proteins. The same proteins were shown to form hydrogels, shedding light on the role of “functional aggregation” in nuclear substructure.

Phase separation provides a mechanism to reduce noise in cells

Science ◽  
2020 ◽  
Vol 367 (6476) ◽  
pp. 464-468 ◽  
Author(s):  
A. Klosin ◽  
F. Oltsch ◽  
T. Harmon ◽  
A. Honigmann ◽  
F. Jülicher ◽  
...  
Keyword(s):  
Signal Processing ◽  
Phase Separation ◽  
Physical Model ◽  
Mammalian Cells ◽  
Protein Concentration ◽  
Liquid Droplets ◽  
Potential Mechanism ◽  
Biological Signal Processing ◽  
Cellular Control ◽  
And Control

Expression of proteins inside cells is noisy, causing variability in protein concentration among identical cells. A central problem in cellular control is how cells cope with this inherent noise. Compartmentalization of proteins through phase separation has been suggested as a potential mechanism to reduce noise, but systematic studies to support this idea have been missing. In this study, we used a physical model that links noise in protein concentration to theory of phase separation to show that liquid droplets can effectively reduce noise. We provide experimental support for noise reduction by phase separation using engineered proteins that form liquid-like compartments in mammalian cells. Thus, phase separation can play an important role in biological signal processing and control.

scholarly journals Enhancement of gene expression noise due to nonspecific transcription factor binding

2019 ◽  
Author(s):  
Supravat Dey ◽  
Mohammad Soltani ◽  
Abhyudai Singh
Keyword(s):  
Gene Expression ◽  
Stochastic Dynamics ◽  
Gene Expression Noise ◽  
Downstream Target ◽  
High Affinity ◽  
Expression Noise ◽  
Degradation Rates ◽  
Poisson Limit ◽  
Random Fluctuations

ABSTRACTThe genome contains several high-affinity non-functional binding sites for transcription factors (TFs) creating a hidden and unexplored layer of gene regulation. We investigate the role of such “decoy sites” in controlling noise (random fluctuations) in the level of a TF that is synthesized in stochastic bursts. Prior studies have assumed that decoy-bound TFs are protected from degradation, and in this case decoys function to buffer noise. Relaxing this assumption to consider arbitrary degradation rates for both bound/unbound TF states, we find rich noise behaviors. For low-affinity decoys, noise in the level of unbound TF always monotonically decreases to the Poisson limit with increasing decoy numbers. In contrast, for high affinity decoys, noise levels first increase with increasing decoy numbers, before decreasing back to the Poisson limit. Interestingly, while protection of bound TFs from degradation slows the time-scale of fluctuations in the unbound TF levels, decay of bounds TFs leads to faster fluctuations and smaller noise propagation to downstream target proteins. In summary, our analysis reveals stochastic dynamics emerging from nonspecific binding of TFs, and highlight the dual role of decoys as attenuators or amplifiers of gene expression noise depending on their binding affinity and stability of the bound TF.

scholarly journals Dual Role for Transforming Growth Factor β-Dependent Signaling in Trypanosoma cruzi Infection of Mammalian Cells

2000 ◽  
Vol 68 (4) ◽  
pp. 2077-2081 ◽  
Author(s):  
Belinda S. Hall ◽  
Miercio A. Pereira
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Trypanosoma Cruzi ◽  
Host Cell ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Transforming Growth Factor Β

ABSTRACT Expression of functional transforming growth factor β (TGF-β) receptors (TβR) is required for the invasion of mammalian cells by the protozoan parasite Trypanosoma cruzi. However, the precise role of this host cell signaling complex in T. cruzi infection is unknown. To investigate the role of the TGF-β signaling pathway, infection levels were studied in the mink lung epithelial cell lines JD1, JM2, and JM3. These cells express inducible mutant TβR1 proteins that cannot induce growth arrest in response to TGF-β but still transmit the signal for TGF-β-dependent gene expression. In the absence of mutant receptor expression, trypomastigotes invaded the cells at a low level. Induction of the mutant receptors caused an increase in infection in all three cell lines, showing that the requirement for TGF-β signaling at invasion can be divorced from TGF-β-induced growth arrest. TGF-β pretreatment of mink lung cells expressing wild-type TβR1 caused a marked enhancement of infection, but no enhancement was seen in JD1, JM2, and JM3 cells, showing that the ability of TGF-β to stimulate infection is associated with growth arrest. Likewise, expression of SMAD7 or SMAD2SA, inhibitors of TGF-β signaling, did not block infection by T. cruzi but did block the enhancement of infection by TGF-β. Taken together, these results show that there is a dual role for TGF-β signaling in T. cruzi infection. The initial invasion of the host cell is independent of both TGF-β-dependent gene expression and growth arrest, but TGF-β stimulation of infection requires a fully functional TGF-β signaling pathway.

scholarly journals Chromosome-wide co-fluctuation of stochastic gene expression in mammalian cells

2019 ◽  
Author(s):  
Mengyi Sun ◽  
Jianzhi Zhang
Keyword(s):  
Gene Expression ◽  
Mammalian Cells ◽  
Three Dimensional ◽  
Sequencing Data ◽  
Chromatin Dynamics ◽  
Gene Expression Noise ◽  
Genes Encoding ◽  
The Face ◽  
Allele Specific ◽  
Genomic Scale

ABSTRACTGene expression is subject to stochastic noise, but to what extent and by which means such stochastic variations are coordinated among different genes are unclear. We hypothesize that neighboring genes on the same chromosome co-fluctuate in expression because of their common chromatin dynamics, and verify it at the genomic scale using allele-specific single-cell RNA-sequencing data of mouse cells. Unexpectedly, the co-fluctuation extends to genes that are over 60 million bases apart. We provide evidence that this long-range effect arises in part from chromatin co-accessibilities of linked loci attributable to three-dimensional proximity, which is much closer intra-chromosomally than inter-chromosomally. We further show that genes encoding components of the same protein complex tend to be chromosomally linked, likely resulting from natural selection for intracellular among-component dosage balance. These findings have implications for both the evolution of genome organization and optimal design of synthetic genomes in the face of gene expression noise.

scholarly journals Role of cell signaling in poxvirus-mediated foreign gene expression in mammalian cells

Vaccine ◽  
2009 ◽  
Vol 27 (22) ◽  
pp. 2994-3006 ◽  
Author(s):  
Ningjie Hu ◽  
Richard Yu ◽  
Cecilia Shikuma ◽  
Bruce Shiramizu ◽  
Mario A. Ostrwoski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Signaling ◽  
Mammalian Cells ◽  
Foreign Gene ◽  
Foreign Gene Expression ◽  
Expression In Mammalian Cells

scholarly journals Translational inhibition and phase separation primes the epigenetic silencing of transposons

2020 ◽  
Author(s):  
Eun Yu Kim ◽  
Ling Wang ◽  
Zhen Lei ◽  
Hui Li ◽  
Wenwen Fan ◽  
...  
Keyword(s):  
Phase Separation ◽  
Epigenetic Silencing ◽  
Regulatory Mechanisms ◽  
Genome Integrity ◽  
Liquid Droplets ◽  
Ribosome Stalling ◽  
Insight Into ◽  
Liquid Liquid Phase Separation

AbstractTransposons are mobile DNAs that can cause fatal mutations. To counteract these genome invaders, the host genomes deploy small interfering (si) RNAs to initiate and establish the epigenetic silencing. However, the regulatory mechanisms for the selective recognition of transposons by the host genomes remain still elusive. Here we show that plant transposon RNAs undergo frequent ribosome stalling caused by their inherently unfavourable codon sequence usage. The ribosome stalling then causes the RNA truncation and the localization to siRNA bodies, which are both critical prerequisites for the siRNA processing. In addition, SGS3, the key protein in the siRNA biogenesis pathway, forms liquid droplets in vitro through its prion-like domains implicating the role of liquid-liquid phase separation in the formation of the siRNA bodies. Our study provides a novel insight into the regulatory mechanisms for the recognition of invasive genetic elements which is essential for the maintenance of genome integrity.

scholarly journals RING1 Interacts with Multiple Polycomb-Group Proteins and Displays Tumorigenic Activity

1999 ◽  
Vol 19 (1) ◽  
pp. 57-68 ◽  
Author(s):  
David P. E. Satijn ◽  
Arie P. Otte
Keyword(s):  
Gene Expression ◽  
Protein Interactions ◽  
Mammalian Cells ◽  
Protein Complexes ◽  
Cellular Transformation ◽  
Polycomb Group ◽  
Expression Levels ◽  
Self Association

ABSTRACT Polycomb-group (PcG) proteins form large multimeric protein complexes that are involved in maintaining the transcriptionally repressive state of genes. Previously, we reported that RING1 interacts with vertebrate Polycomb (Pc) homologs and is associated with or is part of a human PcG complex. However, very little is known about the role of RING1 as a component of the PcG complex. Here we undertake a detailed characterization of RING1 protein-protein interactions. By using directed two-hybrid and in vitro protein-protein analyses, we demonstrate that RING1, besides interacting with the human Pc homolog HPC2, can also interact with itself and with the vertebrate PcG protein BMI1. Distinct domains in the RING1 protein are involved in the self-association and in the interaction with BMI1. Further, we find that the BMI1 protein can also interact with itself. To better understand the role of RING1 in regulating gene expression, we overexpressed the protein in mammalian cells and analyzed differences in gene expression levels. This analysis shows that overexpression of RING1 strongly represses En-2, a mammalian homolog of the well-characterized Drosophila PcG target geneengrailed. Furthermore, RING1 overexpression results in enhanced expression of the proto-oncogenes c-jun and c-fos. The changes in expression levels of these proto-oncogenes are accompanied by cellular transformation, as judged by anchorage-independent growth and the induction of tumors in athymic mice. Our data demonstrate that RING1 interacts with multiple human PcG proteins, indicating an important role for RING1 in the PcG complex. Further, deregulation of RING1 expression leads to oncogenic transformation by deregulation of the expression levels of certain oncogenes.

scholarly journals DNA Methylation and Chromatin: Role(s) of Methyl-CpG-Binding Protein ZBTB38

2018 ◽  
Vol 11 ◽  
pp. 251686571881111 ◽  
Author(s):  
Maud de Dieuleveult ◽  
Benoit Miotto
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Transcription Factors ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Expression Patterns ◽  
Control Of Gene Expression ◽  
Methylated Dna

DNA methylation plays an essential role in the control of gene expression during early stages of development as well as in disease. Although many transcription factors are sensitive to this modification of the DNA, we still do not clearly understand how it contributes to the establishment of proper gene expression patterns. We discuss here the recent findings regarding the biological and molecular function(s) of the transcription factor ZBTB38 that binds methylated DNA sequences in vitro and in cells. We speculate how these findings may help understand the role of DNA methylation and DNA methylation–sensitive transcription factors in mammalian cells.

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