ArticleArthritis & rheumatology (Hoboken, N.J.)2022
Variants on the UBE2L3/YDJC Autoimmune Disease Risk Haplotype Increase UBE2L3 Expression by Modulating CCCTC-Binding Factor and YY1 Binding.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 8 citations in OpenAlex.
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- Unveiling genetic signatures associated with resilience to neonatal diarrhea in lambs through two GWAS approaches.Scientific reports · 2024Article
- Modeling of horizontal pleiotropy identifies possible causal gene expression in systemic lupus erythematosus.Frontiers in lupus · 2023Article
- Systemic lupus erythematosus variants modulate the function of an enhancer upstream ofFrontiers in genetics · 2022Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
objectiveGenetic 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.
methodsWe 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.
resultsOf 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.
conclusionThe UBE2L3/YDJC autoimmune risk haplotype increases UBE2L3 expression through strengthening a YY1-mediated interaction between the UBE2L3 and YDJC promoters.
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