+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

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



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



Biophysical Journal 2019



The transcription factor nuclear factor (NF)-κB promotes inflammatory and stress-responsive gene transcription across a range of cell types in response to the cytokine tumor necrosis factor (TNF). Although NF-κB signaling exhibits significant variability across single cells, some target genes supporting high levels of TNF-inducible transcription exhibit fold-change detection of NF-κB, which may buffer against stochastic variation in signaling molecules. It is unknown whether 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 integrated HIV and the endogenous cytokine gene IL6, 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 transcript abundance at 2 h for low- and high-abundance target genes correlates with similar strength with the fold change in nuclear NF-κB. A computational model of TNF-NF-κB signaling, which implements fold-change detection from competition for binding to κB motifs, could reproduce fold-change detection across the experimentally measured range of transcript outputs. However, multiple model parameters affecting transcription had to be simultaneously varied across promoters to maintain fold-change detection while also matching other trends in the single-cell data for low-abundance transcripts. Our results suggest that cells use multiple biological mechanisms to tune transcriptional output while maintaining robustness of NF-κB fold-change detection.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 066446916

Download citation: RISBibTeXText

PMID: 30704857

DOI: 10.1016/j.bpj.2019.01.011


Related references

Signal-dependent Elk-1 target genes involved in transcript processing and cell migration. Biochimica et Biophysica Acta 1829(10): 1026-1033, 2013

Detection of target gene, or its transcript using oligodeoxynucleotide hybridization probes. Tanpakushitsu Kakusan Koso. Protein, Nucleic Acid, Enzyme 32(7): 988-995, 1987

Colorimetric detection of gene transcript by target-induced three-way junction formation. Talanta 158: 1-5, 2018

Effective knockdown of multiple target genes by expressing the single transcript harbouring multi-cistronic shRNAs. Biochemical and Biophysical Research Communications 396(4): 861-865, 2010

Characterization of an abundant COL9A1 transcript in the cochlea with a novel 3' UTR: Expression studies and detection of miRNA target sequence. Journal of the Association for Research in Otolaryngology 7(2): 160-172, 2006

Transcript levels of genes encoding various glycolytic and fermentation enzymes change in response to abiotic stresses. Plant Science Limerick 146(1): 41-51, 1999

Fold-change estimation of differentially expressed genes using mixture mixed-model. Statistical Applications in Genetics and Molecular Biology 4: Article26, 2006

Reporting FDR analogous confidence intervals for the log fold change of differentially expressed genes. Bmc Bioinformatics 12: 288, 2011

GFOLD: a generalized fold change for ranking differentially expressed genes from RNA-seq data. Bioinformatics 28(21): 2782-2788, 2013

Change detection in urban and rural driving scenes: Effects of target type and safety relevance on change blindness. Accident; Analysis and Prevention 100: 111-122, 2017

Study on the principles of base change in 4-fold degenerate sites of protein coding genes. Yi Chuan Xue Bao 23(5): 403-408, 1996

Fold change rank ordering statistics: a new method for detecting differentially expressed genes. Bmc Bioinformatics 15: 14, 2014

Optimal Regulatory Circuit Topologies for Fold-Change Detection. Cell Systems 4(2): 171-181.E8, 2017

Synthetic circuit for exact adaptation and fold-change detection. Nucleic Acids Research 42(9): 6078-6089, 2014

The kdgRKAT operon of Bacillus subtilis: detection of the transcript and regulation by the kdgR and ccpA genes. Microbiology 144: 3111-3118, 1998