An Enhancer Element Harboring Variants Associated with Systemic Lupus Erythematosus Engages the TNFAIP3 Promoter to Influence A20 Expression

2013-09-16 14:26:47

PLoS Genetics 9(9): e1003750. DOI:10.1371/journal.pgen.1003750

Shaofeng Wang, Feng Wen, Graham B. Wiley, Michael T. Kinter, Patrick M. Gaffney

Author Summary

A key objective of human genetics is the identification and characterization of variants responsible for association with complex diseases. A pair of single nucleotide polymorphisms (rs148314165, rs200820567) 42 kb downstream from the promoter of TNFAIP3, have been proposed as the variants responsible for association with systemic lupus erythematosus based on comprehensive genetic and bioinformatic analyses. TNFAIP3 encodes for the ubiquitin-editing enzyme, A20, which plays a central role in maintaining immune system homeostasis through restriction of NF-κB signaling. Cells that carry this risk haplotype express low levels of TNFAIP3 compared to cells carrying the nonrisk haplotype. How the risk alleles of rs148314165 and rs200820567 might influence low TNFAIP3 expression is unknown. In this paper, we demonstrate that these variants reside in an enhancer element that binds NF-κB and SATB1 enabling the interaction of the enhancer with the TNFAIP3 promoter through long-range DNA looping. Impaired binding of NF-κB directly to the risk alleles or shRNA-mediated knockdown of SATB1 inhibits interaction of the enhancer with the TNFAIP3 promoter resulting in reduced A20 expression. These results clarify the functional mechanism by which rs148314165 and rs200820567 attenuate A20 expression and support a causal role for these variants in the predisposition to autoimmune disease.

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