scholarly journals Fold-Change Detection of NF-κB at Target Genes with Different Transcript Outputs

2019 ◽  
Vol 116 (4) ◽  
pp. 709-724 ◽  
Author(s):  
Victor C. Wong ◽  
Shibin Mathew ◽  
Ramesh Ramji ◽  
Suzanne Gaudet ◽  
Kathryn Miller-Jensen
Keyword(s):  
Change Detection ◽  
Target Genes ◽  
Fold Change ◽  
Fold Change Detection

scholarly journals Fold-change detection of NF-κB at target genes with different transcript outputs

2018 ◽  
Author(s):  
V. C. Wong ◽  
R. Ramji ◽  
S. Gaudet ◽  
K. Miller-Jensen
Keyword(s):  
Change Detection ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Single Cells ◽  
Cell Types ◽  
Fold Change ◽  
Stochastic Variation ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Fold Change Detection

AbstractThe transcription factor NF-κB promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor-α (TNF). Although NF-κB signaling exhibits significant variability across single cells, some target genes exhibit fold-change detection of NF-κB, which may buffer against stochastic variation in signaling molecules. However, this observation was made at target genes supporting high levels of TNF-inducible transcription. It is unknown if fold-change detection is maintained at NF-κB target genes with low levels of TNF-inducible transcription, for which stochastic promoter events may be more pronounced. Here we used a microfluidic cell-trapping device to measure how TNF-induced activation of NF-κB controls transcription in single Jurkat T cells at the promoters of integratedHIVand the endogenous cytokine geneIL6, which produce only a few transcripts per cell. We tracked TNF-stimulated NF-κB RelA nuclear translocation by live-cell imaging and then quantified transcript number by RNA FISH in the same cell. We found that TNF-induced transcription correlates with fold change in nuclear NF-κB with similar strength at low versus high abundance target genes. A computational model of TNF-NF-κB signaling, which implements fold-change detection from competition for binding to κB motifs, was sufficient to reproduce fold-change detection across the experimentally measured range of transcript outputs. Nevertheless, we found that gene-specific trends in transcriptional noise and levels of promoter-bound NF-κB predicted by the model were inconsistent with our experimental observations at low abundance gene targets. Our results reveal a gap in our understanding of RelA-mediated transcription for low abundance transcripts and suggest that cells use additional biological mechanisms to maintain robustness of NF-κB fold-change detection while tuning transcriptional output.

scholarly journals An empirical bayesian approach for testing gene expression fold change and its application in detecting global dosage effects

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Zhenxing Guo ◽  
Ying Cui ◽  
Xiaowen Shi ◽  
James A Birchler ◽  
Igor Albizua ◽  
...  
Keyword(s):  
Gene Expression ◽  
Change Detection ◽  
Bayesian Approach ◽  
Variance Estimation ◽  
T Test ◽  
Fold Change ◽  
Empirical Bayesian ◽  
Biological Studies ◽  
Fold Change Detection ◽  
Empirical Bayesian Approach

Abstract We are motivated by biological studies intended to understand global gene expression fold change. Biologists have generally adopted a fixed cutoff to determine the significance of fold changes in gene expression studies (e.g. by using an observed fold change equal to two as a fixed threshold). Scientists can also use a t-test or a modified differential expression test to assess the significance of fold changes. However, these methods either fail to take advantage of the high dimensionality of gene expression data or fail to test fold change directly. Our research develops a new empirical Bayesian approach to substantially improve the power and accuracy of fold-change detection. Specifically, we more accurately estimate gene-wise error variation in the log of fold change. We then adopt a t-test with adjusted degrees of freedom for significance assessment. We apply our method to a dosage study in Arabidopsis and a Down syndrome study in humans to illustrate the utility of our approach. We also present a simulation study based on real datasets to demonstrate the accuracy of our method relative to error variance estimation and power in fold-change detection. Our developed R package with a detailed user manual is publicly available on GitHub at https://github.com/cuiyingbeicheng/Foldseq.

scholarly journals Synthetic circuit for exact adaptation and fold-change detection

2014 ◽  
Vol 42 (9) ◽  
pp. 6078-6089 ◽  
Author(s):  
Jongmin Kim ◽  
Ishan Khetarpal ◽  
Shaunak Sen ◽  
Richard M. Murray
Keyword(s):  
Change Detection ◽  
Fold Change ◽  
Synthetic Circuit ◽  
Fold Change Detection

scholarly journals Optimal Regulatory Circuit Topologies for Fold-Change Detection

Cell Systems ◽  
2017 ◽  
Vol 4 (2) ◽  
pp. 171-181.e8 ◽  
Author(s):  
Miri Adler ◽  
Pablo Szekely ◽  
Avi Mayo ◽  
Uri Alon
Keyword(s):  
Change Detection ◽  
Fold Change ◽  
Regulatory Circuit ◽  
Fold Change Detection

scholarly journals Sensing relative signal in the Tgf-β/Smad pathway

2017 ◽  
Vol 114 (14) ◽  
pp. E2975-E2982 ◽  
Author(s):  
Christopher L. Frick ◽  
Clare Yarka ◽  
Harry Nunns ◽  
Lea Goentoro
Keyword(s):  
Single Molecule ◽  
Target Genes ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Fold Change ◽  
Smad Pathway ◽  
Smad Proteins ◽  
Ligand Stimulation ◽  
Change Response ◽  
Fold Change Detection

How signaling pathways function reliably despite cellular variation remains a question in many systems. In the transforming growth factor-β (Tgf-β) pathway, exposure to ligand stimulates nuclear localization of Smad proteins, which then regulate target gene expression. Examining Smad3 dynamics in live reporter cells, we found evidence for fold-change detection. Although the level of nuclear Smad3 varied across cells, the fold change in the level of nuclear Smad3 was a more precise outcome of ligand stimulation. The precision of the fold-change response was observed throughout the signaling duration and across Tgf-β doses, and significantly increased the information transduction capacity of the pathway. Using single-molecule FISH, we further observed that expression of Smad3 target genes (ctgf, snai1, and wnt9a) correlated more strongly with the fold change, rather than the level, of nuclear Smad3. These findings suggest that some target genes sense Smad3 level relative to background, as a strategy for coping with cellular noise.

scholarly journals Incoherent feedforward motifs as immune change detectors

2015 ◽  
Author(s):  
Eduardo Sontag
Keyword(s):  
Change Detection ◽  
Scale Invariance ◽  
Fold Change ◽  
Fold Change Detection

We speculate that incoherent feedforward loops may be phenomenologically involved in self/nonself discrimination in immune-infection and immune-tumor interactions, acting as "change detectors". In turn, this may result in logarithmic sensing (Weber phenomenon) and even scale invariance (fold-change detection).

Sign in / Sign up

Export Citation Format

Share Document