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https://www.selleckchem.com/products/ms-275.html and anterior-temporal networks in Alzheimer's disease pathophysiology and clinical symptoms. ANN NEUROL 2021. Genetic variants spanning the ubiquitin-conjugating enzyme E2 L3 (UBE2L3) gene are associated with increased expression of the UBE2L3-encoded E2 ubiquitin-conjugating enzyme, UbcH7, that facilitates activation of proinflammatory NF-κB signaling, and susceptibility to autoimmune diseases. This study aims to delineate how genetic variants carried on the UBE2L3-YDJC autoimmune risk haplotype function to drive hypermorphic UBE2L3 expression. 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 (3C)-qPCR, ChIP-qPCR, and siRNA knockdown assays were performed on patient-derived EBV-transformed B cells homozygous for the UBE2L3-YDJC non-risk or risk haplotype to determine if the risk haplotype increases UBE2L3 expression by altering the regulatory chromatin architecture in the region. Five of the seven prioritized variants demonstrated allele-specific increases in nuclear protein binding affinity and regulatory activity. HiChIP and 3C-qPCR uncovered a long-range interaction between the UBE2L3 promoter (rs140490, rs140491, rs11089620) and downstream YDJC promoter (rs3747093) that was strengthened in the presence of the UBE2L3-YDJC risk haplotype, and correlated with the loss of CTCF binding and gain of YY1 binding at the risk alleles. Depleting YY1 by siRNA disrupted the long-range interaction between the two promoters and reduced UBE2L3 expression. The UBE2L3-YDJC autoimmune risk haplotype increases UBE2L3 expression through strengthening a YY1-mediated interaction between the UBE2L3 and YDJC promoters. The UBE2L3-YDJC autoimmune risk haplotype increases UBE2L3 expression through strengthening a YY1

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