Article ; Online: TNF stimulation primarily modulates transcriptional burst size of NF-κB-regulated genes.
2021 Volume 17, Issue 7, Page(s) e10127
Abstract: Cell-to-cell heterogeneity is a feature of the tumor necrosis factor (TNF)-stimulated inflammatory response mediated by the transcription factor NF-κB, motivating an exploration of the underlying sources of this noise. Here, we combined single-transcript ...
| Abstract | Cell-to-cell heterogeneity is a feature of the tumor necrosis factor (TNF)-stimulated inflammatory response mediated by the transcription factor NF-κB, motivating an exploration of the underlying sources of this noise. Here, we combined single-transcript measurements with computational models to study transcriptional noise at six NF-κB-regulated inflammatory genes. In the basal state, NF-κB-target genes displayed an inverse correlation between mean and noise characteristic of transcriptional bursting. By analyzing transcript distributions with a bursting model, we found that TNF primarily activated transcription by increasing burst size while maintaining burst frequency for gene promoters with relatively high basal histone 3 acetylation (AcH3) that marks open chromatin environments. For promoters with lower basal AcH3 or when AcH3 was decreased with a small molecule drug, the contribution of burst frequency to TNF activation increased. Finally, we used a mathematical model to show that TNF positive feedback amplified gene expression noise resulting from burst size-mediated transcription, leading to a subset of cells with high TNF protein expression. Our results reveal potential sources of noise underlying intercellular heterogeneity in the TNF-mediated inflammatory response. |
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| MeSH term(s) | Acetylation ; Gene Expression Regulation ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Promoter Regions, Genetic ; Tumor Necrosis Factor-alpha/genetics |
| Chemical Substances | NF-kappa B ; Tumor Necrosis Factor-alpha |
| Language | English |
| Publishing date | 2021-07-19 |
| Publishing country | England |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. |
| ZDB-ID | 2193510-5 |
| ISSN | 1744-4292 ; 1744-4292 |
| ISSN (online) | 1744-4292 |
| ISSN | 1744-4292 |
| DOI | 10.15252/msb.202010127 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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