Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models.

TitleDissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models.
Publication TypeJournal Article
Year of Publication2018
AuthorsSokhi UK, Liber MP, Frye L, Park S, Kang K, Pannellini T, Zhao B, Norinsky R, Ivashkiv LB, Gong S
JournalNat Commun
Date Published2018 02 13
KeywordsAnimals, Arthritis, Rheumatoid, Autoimmune Diseases, Autoimmunity, Base Sequence, Cells, Cultured, Enhancer Elements, Genetic, Female, Gene Expression Regulation, Genetic Predisposition to Disease, HEK293 Cells, Humans, Male, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Polymorphism, Single Nucleotide, Tumor Necrosis Factor alpha-Induced Protein 3

Enhancers regulate gene expression and have been linked with disease pathogenesis. Little is known about enhancers that regulate human disease-associated genes in primary cells relevant for pathogenesis. Here we use BAC transgenics and genome editing to dissect, in vivo and in primary immune cells, enhancers that regulate human TNFAIP3, which encodes A20 and is linked with autoimmune diseases. A20 expression is dependent on a topologically associating subdomain (sub-TAD) that harbors four enhancers, while another >20 enhancers in the A20 locus are redundant. This sub-TAD contains cell- and activation-specific enhancers, including an enhancer (termed TT>A) harboring a proposed causal SLE-associated SNV. Deletion of the sub-TAD or the TT>A enhancer results in enhanced inflammatory responses, autoantibody production, and inflammatory arthritis, thus establishing functional importance in vivo and linking enhancers with a specific disease phenotype. These findings provide insights into enhancers that regulate human A20 expression to prevent inflammatory pathology and autoimmunity.

Alternate JournalNat Commun
PubMed ID29440643
PubMed Central IDPMC5811492
Grant ListR01 AR046713 / AR / NIAMS NIH HHS / United States
R01 AR071463 / AR / NIAMS NIH HHS / United States
R01 AR068970 / AR / NIAMS NIH HHS / United States
R01 AI046712 / AI / NIAID NIH HHS / United States
R01 AR050401 / AR / NIAMS NIH HHS / United States