{"doi":"10.1101/2020.11.16.384297","title":"TNF stimulation primarily modulates transcriptional burst size of NF-κB-regulated genes","abstract":"Abstract Cell-to-cell heterogeneity is a characteristic 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. TNF stimulation increased transcription while maintaining noise, except for the most repressed genes. By fitting transcript distributions to a two-state model of promoter activity, we found that TNF primarily stimulated transcription by increasing burst size while maintaining burst frequency. Burst size increases were associated with enrichment of initiated-but-paused RNA polymerase II at the promoter, and blocking the release of paused RNAPII with a small molecule inhibitor decreased TNF-stimulated burst size. Finally, we used a mathematical model to show that TNF positive feedback further amplified gene expression noise resulting from burst-size mediated transcription, leading to diverse TNF functional outputs. Our results reveal potential sources of noise underlying intercellular heterogeneity in the TNF-mediated inflammatory response.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125588,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":572240,"name":"Victor C. Wong","orcid":"0000-0002-7060-960X","position":1,"is_corresponding":false},{"id":572241,"name":"M. Elise Bullock","orcid":"0000-0002-7876-4938","position":2,"is_corresponding":false},{"id":572242,"name":"Suzanne Gaudet","orcid":"0000-0002-5701-2825","position":3,"is_corresponding":false},{"id":566848,"name":"Kathryn Miller‐Jensen","orcid":"0000-0002-7233-0100","position":4,"is_corresponding":false},{"id":572239,"name":"Victor L. Bass","orcid":"0000-0003-2850-7949","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-18T23:15:19.482428Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}