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

Upneet K. Sokhi, Mark P. Liber, Laura Frye, Sungho Park, Kyuho Kang, Tania Pannellini, Baohong Zhao, Rada Norinsky, Lionel B. Ivashkiv () and Shiaoching Gong ()
Additional contact information
Upneet K. Sokhi: Hospital for Special Surgery
Mark P. Liber: Hospital for Special Surgery
Laura Frye: Hospital for Special Surgery
Sungho Park: Hospital for Special Surgery
Kyuho Kang: Hospital for Special Surgery
Tania Pannellini: Hospital for Special Surgery
Baohong Zhao: Hospital for Special Surgery
Rada Norinsky: Rockefeller University
Lionel B. Ivashkiv: Hospital for Special Surgery
Shiaoching Gong: Hospital for Special Surgery

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03081-7

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