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

Overview

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.

publication date

  • February 13, 2018

Research

keywords

  • Autoimmune Diseases
  • Enhancer Elements, Genetic
  • Genetic Predisposition to Disease
  • Tumor Necrosis Factor alpha-Induced Protein 3

Identity

PubMed Central ID

  • PMC5811492

Scopus Document Identifier

  • 85042047453

Digital Object Identifier (DOI)

  • 10.1038/nprot.2011.444

PubMed ID

  • 29440643

Additional Document Info

volume

  • 9

issue

  • 1