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We undertook this study to delineate how genetic variants carried on the <jats:italic>UBE2L3\/YDJC<\/jats:italic> autoimmune risk haplotype function to drive hypermorphic <jats:italic>UBE2L3<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We used bioinformatic analyses, electrophoretic mobility shift assays, and luciferase reporter assays to identify and functionally characterize allele\u2010specific effects of risk variants positioned in chromatin accessible regions of immune cells. Chromatin conformation capture with quantitative polymerase chain reaction (3C\u2010qPCR), chromatin immunoprecipitation (ChIP)\u2013qPCR, and small interfering RNA (siRNA) knockdown assays were performed on patient\u2010derived Epstein\u2010Barr virus\u2013transformed B cells homozygous for the <jats:italic>UBE2L3<\/jats:italic>\/<jats:italic>YDJC<\/jats:italic> nonrisk or risk haplotype to determine if the risk haplotype increases <jats:italic>UBE2L3<\/jats:italic> expression by altering the regulatory chromatin architecture in the region.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of the 7 prioritized variants, 5 demonstrated allele\u2010specific increases in nuclear protein binding affinity and regulatory activity. High\u2010throughput sequencing of chromosome conformation capture coupled with ChIP (HiChIP) and 3C\u2010qPCR uncovered a long\u2010range interaction between the <jats:italic>UBE2L3<\/jats:italic> promoter (rs140490, rs140491, rs11089620) and the downstream <jats:italic>YDJC<\/jats:italic> promoter (rs3747093) that was strengthened in the presence of the <jats:italic>UBE2L3<\/jats:italic>\/<jats:italic>YDJC<\/jats:italic> risk haplotype, and correlated with the loss of CCCTC\u2010binding factor (CTCF) and gain of YY1 binding at the risk alleles. Depleting YY1 by siRNA disrupted the long\u2010range interaction between the 2 promoters and reduced <jats:italic>UBE2L3<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The <jats:italic>UBE2L3<\/jats:italic>\/<jats:italic>YDJC<\/jats:italic> autoimmune risk haplotype increases <jats:italic>UBE2L3<\/jats:italic> expression through strengthening a YY1\u2010mediated interaction between the <jats:italic>UBE2L3<\/jats:italic> and <jats:italic>YDJC<\/jats:italic> promoters.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41925","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T05:49:20Z","timestamp":1626673760000},"page":"163-173","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"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\u2010Binding<\/scp> Factor and YY1 Binding"],"prefix":"10.1002","volume":"74","author":[{"given":"Jaanam","family":"Gopalakrishnan","sequence":"first","affiliation":[{"name":"Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kandice L.","family":"Tessneer","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Fu","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Pasula","sequence":"additional","affiliation":[{"name":"Oklahoma Medical Research Foundation  Oklahoma City"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard 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