{"doi":"10.1126/scitranslmed.adp1720","title":"An autoimmune transcriptional circuit drives FOXP3\n            <sup>+</sup>\n            regulatory T cell dysfunction","abstract":"Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4<sup>+</sup>FOXP3<sup>+</sup> regulatory T cells (T<sub>regs</sub>) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of T<sub>regs</sub> in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long <i>PRDM1</i>, which led to destabilization of forkhead box P3 (FOXP3) and T<sub>reg</sub> dysfunction. This aberrant <i>PRDM1-S/SGK1</i> axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in T<sub>regs</sub> from individuals with MS revealed enriched activating protein-1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of <i>PRDM1-S</i> expression and T<sub>reg</sub> dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of <i>PRDM1-S</i> and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional T<sub>regs</sub> in autoimmune diseases.","journal":"Science Translational Medicine","year":2024,"id":4615,"datarank":0.5341065139916925,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.07742814833317904,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.07742814833317904,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":19,"citers_with_citation_signal":10,"citers_with_endowment":10,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0418,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-08-28","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":49153,"name":"Matthew R. Lincoln","orcid":"0000-0003-2962-6253","position":1,"is_corresponding":false},{"id":18245,"name":"Liang He","orcid":"0000-0001-6711-2021","position":2,"is_corresponding":false},{"id":7736,"name":"Yongjin P. Park","orcid":"0000-0001-8915-2876","position":3,"is_corresponding":false},{"id":49154,"name":"Mineto Ota","orcid":"0000-0003-4552-8573","position":4,"is_corresponding":false},{"id":49155,"name":"Akiko Oguchi","orcid":"0000-0002-9948-6295","position":5,"is_corresponding":false},{"id":49156,"name":"Raku Son","orcid":"0000-0002-9250-9474","position":6,"is_corresponding":false},{"id":49157,"name":"Alice Yi","orcid":"0009-0009-9715-3612","position":7,"is_corresponding":false},{"id":49158,"name":"Helen A. Stillwell","orcid":"0000-0003-2178-3473","position":8,"is_corresponding":false},{"id":49159,"name":"Greta A. Leissa","orcid":"0000-0001-6985-9321","position":9,"is_corresponding":false},{"id":49160,"name":"Keishi Fujio","orcid":"0000-0001-7276-5254","position":10,"is_corresponding":false},{"id":49161,"name":"Yasuhiro Murakawa","orcid":"0000-0002-5415-1352","position":11,"is_corresponding":false},{"id":49162,"name":"Alexander M. Kulminski","orcid":"0000-0002-0205-8228","position":12,"is_corresponding":false},{"id":866,"name":"Charles B. Epstein","orcid":"0000-0001-8358-8345","position":13,"is_corresponding":false},{"id":42925,"name":"Louis Philip Benoit Bouvrette","orcid":"0000-0003-2726-5669","position":14,"is_corresponding":false},{"id":14693,"name":"Sharon L. R. Kardia","orcid":"0000-0002-9853-3379","position":15,"is_corresponding":false},{"id":37332,"name":"David A. Hafler","orcid":"0000-0003-4664-535X","position":16,"is_corresponding":false},{"id":49152,"name":"Tomokazu S. Sumida","orcid":"0000-0002-9806-2642","position":0,"is_corresponding":true}],"reference_count":118,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-03-01T18:20:47.508186Z","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":[]}