{"doi":"10.1101/2021.10.03.462944","title":"PAX3-FOXO1 coordinates enhancer architecture, eRNA transcription, and RNA polymerase pause release at select gene targets","abstract":"Abstract Transcriptional control is a highly dynamic process that changes rapidly in response to various cellular and extracellular cues 1 . Thus, it is difficult to achieve a mechanistic understanding of transcription factor function using traditional genetic deletion or RNAi methods, because these slow approaches make it challenging to distinguish direct from indirect transcriptional effects. Here, we used a chemical-genetic approach to rapidly degrade a canonical transcriptional activator, PAX3-FOXO1 2-6 to define how the t(2;13)(q35;q14) disrupts normal gene expression programs to trigger cancer. By coupling rapid protein degradation with the analysis of nascent transcription over short time courses, we identified a core transcriptional network that rapidly collapsed upon PAX3-FOXO1 degradation. Moreover, loss of PAX3-FOXO1 impaired RNA polymerase pause release and transcription elongation at regulated gene targets. The activity of PAX3-FOXO1 at enhancers controlling this core network was surprisingly selective and often only a single element within a complex super-enhancer was affected. In addition, fusion of the endogenous PAX3-FOXO1 with APEX2 identified proteins in close proximity with PAX3-FOXO1, including ARID1A and MYOD1. We found that continued expression of PAX3-FOXO1 was required to maintain chromatin accessibility and allow neighboring DNA binding proteins and chromatin remodeling complexes to associate with this small number of regulated enhancers. Overall, this work provides a detailed mechanism by which PAX3-FOXO1 maintains an oncogenic transcriptional regulatory network.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217893,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9568,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":775799,"name":"Jing Wang","orcid":"0000-0003-0012-7426","position":1,"is_corresponding":false},{"id":289616,"name":"Qi Liu","orcid":"0000-0002-0596-5579","position":2,"is_corresponding":false},{"id":276954,"name":"W. Hayes McDonald","orcid":"0000-0002-3510-426X","position":3,"is_corresponding":false},{"id":557427,"name":"Monica Bomber","orcid":"0000-0002-9489-4484","position":4,"is_corresponding":false},{"id":728897,"name":"Hillary M. Layden","orcid":"0000-0001-8583-620X","position":5,"is_corresponding":false},{"id":558214,"name":"Jacob Ellis","orcid":null,"position":6,"is_corresponding":false},{"id":516258,"name":"Scott C. Borinstein","orcid":"0000-0002-1721-1520","position":7,"is_corresponding":false},{"id":333583,"name":"Scott W. Hiebert","orcid":"0000-0001-5621-1454","position":8,"is_corresponding":false},{"id":333580,"name":"Kristy R. Stengel","orcid":"0000-0002-8330-5744","position":9,"is_corresponding":false},{"id":364078,"name":"Susu Zhang","orcid":"0000-0003-0751-6467","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-18T23:53:24.683898Z","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":[]}