Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models
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,...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811492/ https://www.ncbi.nlm.nih.gov/pubmed/29440643 http://dx.doi.org/10.1038/s41467-018-03081-7 |
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author | Sokhi, Upneet K. Liber, Mark P. Frye, Laura Park, Sungho Kang, Kyuho Pannellini, Tania Zhao, Baohong Norinsky, Rada Ivashkiv, Lionel B. Gong, Shiaoching |
author_facet | Sokhi, Upneet K. Liber, Mark P. Frye, Laura Park, Sungho Kang, Kyuho Pannellini, Tania Zhao, Baohong Norinsky, Rada Ivashkiv, Lionel B. Gong, Shiaoching |
author_sort | Sokhi, Upneet K. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5811492 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-58114922018-02-15 Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models Sokhi, Upneet K. Liber, Mark P. Frye, Laura Park, Sungho Kang, Kyuho Pannellini, Tania Zhao, Baohong Norinsky, Rada Ivashkiv, Lionel B. Gong, Shiaoching Nat Commun Article 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. Nature Publishing Group UK 2018-02-13 /pmc/articles/PMC5811492/ /pubmed/29440643 http://dx.doi.org/10.1038/s41467-018-03081-7 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Sokhi, Upneet K. Liber, Mark P. Frye, Laura Park, Sungho Kang, Kyuho Pannellini, Tania Zhao, Baohong Norinsky, Rada Ivashkiv, Lionel B. Gong, Shiaoching Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title | Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title_full | Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title_fullStr | Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title_full_unstemmed | Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title_short | Dissection and function of autoimmunity-associated TNFAIP3 (A20) gene enhancers in humanized mouse models |
title_sort | dissection and function of autoimmunity-associated tnfaip3 (a20) gene enhancers in humanized mouse models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811492/ https://www.ncbi.nlm.nih.gov/pubmed/29440643 http://dx.doi.org/10.1038/s41467-018-03081-7 |
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