{"doi":"10.1002/art.41925","title":"Variants on the <scp><i>UBE2L3</i></scp>/<scp><i>YDJC</i></scp> Autoimmune Disease Risk Haplotype Increase <scp><i>UBE2L3</i></scp> Expression by Modulating <scp>CCCTC‐Binding</scp> Factor and YY1 Binding","abstract":"OBJECTIVE: Genetic variants spanning UBE2L3 are associated with increased expression of the UBE2L3-encoded E2 ubiquitin-conjugating enzyme H7 (UbcH7), which facilitates activation of proinflammatory NF-κB signaling and susceptibility to autoimmune diseases. We undertook this study to delineate how genetic variants carried on the UBE2L3/YDJC autoimmune risk haplotype function to drive hypermorphic UBE2L3 expression. METHODS: We used bioinformatic analyses, electrophoretic mobility shift assays, and luciferase reporter assays to identify and functionally characterize allele-specific effects of risk variants positioned in chromatin accessible regions of immune cells. Chromatin conformation capture with quantitative polymerase chain reaction (3C-qPCR), chromatin immunoprecipitation (ChIP)-qPCR, and small interfering RNA (siRNA) knockdown assays were performed on patient-derived Epstein-Barr virus-transformed B cells homozygous for the UBE2L3/YDJC nonrisk or risk haplotype to determine if the risk haplotype increases UBE2L3 expression by altering the regulatory chromatin architecture in the region. RESULTS: Of the 7 prioritized variants, 5 demonstrated allele-specific increases in nuclear protein binding affinity and regulatory activity. High-throughput sequencing of chromosome conformation capture coupled with ChIP (HiChIP) and 3C-qPCR uncovered a long-range interaction between the UBE2L3 promoter (rs140490, rs140491, rs11089620) and the downstream YDJC promoter (rs3747093) that was strengthened in the presence of the UBE2L3/YDJC risk haplotype, and correlated with the loss of CCCTC-binding factor (CTCF) and gain of YY1 binding at the risk alleles. Depleting YY1 by siRNA disrupted the long-range interaction between the 2 promoters and reduced UBE2L3 expression. CONCLUSION: The UBE2L3/YDJC autoimmune risk haplotype increases UBE2L3 expression through strengthening a YY1-mediated interaction between the UBE2L3 and YDJC promoters.","journal":"Arthritis & Rheumatology","year":2021,"id":195647,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":767035,"name":"Kandice L. Tessneer","orcid":"0000-0002-9268-1653","position":1,"is_corresponding":false},{"id":733459,"name":"Yao Fu","orcid":"0000-0003-2348-4872","position":2,"is_corresponding":false},{"id":767036,"name":"Satish Pasula","orcid":"0000-0002-8288-9207","position":3,"is_corresponding":false},{"id":456162,"name":"Richard Pelikan","orcid":"0000-0001-9674-7341","position":4,"is_corresponding":false},{"id":367555,"name":"Jennifer A. Kelly","orcid":"0000-0002-3203-2467","position":5,"is_corresponding":false},{"id":356137,"name":"Graham B. Wiley","orcid":"0000-0003-1757-6578","position":6,"is_corresponding":false},{"id":73872,"name":"Patrick M. Gaffney","orcid":"0000-0002-1580-869X","position":7,"is_corresponding":false},{"id":767613,"name":"Jaanam Gopalakrishnan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:50:07.691929Z","pmid":"34279042","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":[]}