{"doi":"10.3389/fimmu.2022.789349","title":"SOX4 and RELA Function as Transcriptional Partners to Regulate the Expression of TNF- Responsive Genes in Fibroblast-Like Synoviocytes","abstract":"SOX4 belongs to the group C of the SOX transcription factor family. It is a critical mediator of tumor necrosis factor alpha (TNF)-induced transformation of fibroblast-like s-ynoviocytes (FLS) in arthritis. In this study we investigated the genome wide association between the DNA binding and transcriptional activities of SOX4 and the NF-kappaB signaling transcription factor RELA/p65 downstream of TNF signaling. We used ChIP-seq assays in mouse FLS to compare the global DNA binding profiles of SOX4 and RELA. RNA-seq of TNF-induced wildtype and SoxC -knockout FLS was used to identify the SOX4-dependent and independent aspects of the TNF-regulated transcriptome. We found that SOX4 and RELA physically interact with each other on the chromatin. Interestingly, ChIP-seq assays revealed that 70.4% of SOX4 peak summits were within 50bp of the RELA peak summits suggesting that both proteins bind in close-proximity on regulatory sequences, enabling them to co-operatively regulate gene expression. By integrating the ChIP-seq results with RNA-seq from SoxC -knockout FLS we identified a set of TNF-responsive genes that are targets of the RELA-SOX4 transcriptional complex. These TNF-responsive and RELA-SOX4-depenedent genes included inflammation mediators, histone remodeling enzymes and components of the AP-1 signaling pathway. We also identified an autoregulatory mode of SoxC gene expression that involves a TNF-mediated switch from RELA binding to SOX4 binding in the 3’ UTR of Sox4 and Sox11 genes. In conclusion, our results show that SOX4 and RELA together orchestrate a multimodal regulation of gene expression downstream of TNF signaling. Their interdependent activities play a pivotal role in the transformation of FLS in arthritis and in the inflammatory pathology of diverse tissues where RELA and SOX4 are co-expressed.","journal":"Frontiers in Immunology","year":2022,"id":255268,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":374180,"name":"Sergio Ramírez-Pérez","orcid":"0000-0002-3130-8695","position":1,"is_corresponding":false},{"id":903008,"name":"Shuo Niu","orcid":"0000-0003-1137-0237","position":2,"is_corresponding":false},{"id":375343,"name":"Umesh Gangishetti","orcid":null,"position":3,"is_corresponding":false},{"id":309043,"name":"Hicham Drissi","orcid":"0000-0002-3322-281X","position":4,"is_corresponding":false},{"id":374181,"name":"Pallavi Bhattaram","orcid":"0000-0002-9017-6936","position":5,"is_corresponding":false},{"id":375344,"name":"Kyle M. Jones","orcid":null,"position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T00:25:12.987829Z","pmid":"35529852","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":[]}