TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes
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 mode...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-07-01
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| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/msb.202010127 |
| _version_ | 1797284655809953792 |
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| author | Victor L Bass Victor C Wong M Elise Bullock Suzanne Gaudet Kathryn Miller‐Jensen |
| author_facet | Victor L Bass Victor C Wong M Elise Bullock Suzanne Gaudet Kathryn Miller‐Jensen |
| author_sort | Victor L Bass |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T17:51:33Z |
| format | Article |
| id | doaj.art-23d5bd0087c943f2b2e690d7208ecb52 |
| institution | Directory Open Access Journal |
| issn | 1744-4292 |
| language | English |
| last_indexed | 2024-03-07T17:51:33Z |
| publishDate | 2021-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj.art-23d5bd0087c943f2b2e690d7208ecb522024-03-02T13:55:38ZengSpringer NatureMolecular Systems Biology1744-42922021-07-01177n/an/a10.15252/msb.202010127TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genesVictor L Bass0Victor C Wong1M Elise Bullock2Suzanne Gaudet3Kathryn Miller‐Jensen4Department of Molecular, Cellular, and Developmental Biology Yale University New Haven CT USADepartment of Molecular, Cellular, and Developmental Biology Yale University New Haven CT USADepartment of Biomedical Engineering Yale University New Haven CT USADepartment of Cancer Biology and Center for Cancer Systems Biology Dana‐Farber Cancer Institute Boston MA USADepartment of Molecular, Cellular, and Developmental Biology Yale University New Haven CT USAAbstract 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.https://doi.org/10.15252/msb.202010127inflammationNF‐κBTNFtranscriptional bursting |
| spellingShingle | Victor L Bass Victor C Wong M Elise Bullock Suzanne Gaudet Kathryn Miller‐Jensen TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes Molecular Systems Biology inflammation NF‐κB TNF transcriptional bursting |
| title | TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes |
| title_full | TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes |
| title_fullStr | TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes |
| title_full_unstemmed | TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes |
| title_short | TNF stimulation primarily modulates transcriptional burst size of NF‐κB‐regulated genes |
| title_sort | tnf stimulation primarily modulates transcriptional burst size of nf κb regulated genes |
| topic | inflammation NF‐κB TNF transcriptional bursting |
| url | https://doi.org/10.15252/msb.202010127 |
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