Resolving mechanisms of immune‐mediated disease in primary CD4 T cells
Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adap...
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| Format: | Article |
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Springer Nature
2020-04-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202012112 |
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| author | Christophe Bourges Abigail F Groff Oliver S Burren Chiara Gerhardinger Kaia Mattioli Anna Hutchinson Theodore Hu Tanmay Anand Madeline W Epping Chris Wallace Kenneth GC Smith John L Rinn James C Lee |
| author_facet | Christophe Bourges Abigail F Groff Oliver S Burren Chiara Gerhardinger Kaia Mattioli Anna Hutchinson Theodore Hu Tanmay Anand Madeline W Epping Chris Wallace Kenneth GC Smith John L Rinn James C Lee |
| author_sort | Christophe Bourges |
| collection | DOAJ |
| description | Abstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune‐mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune‐mediated diseases but cannot be fine‐mapped. By studying the lead expression‐modulating SNP, we uncovered an NF‐κB‐driven regulatory circuit which constrains T‐cell activation through the dynamic formation of a super‐enhancer that upregulates TNFAIP3 (A20), a key NF‐κB inhibitor. In activated T cells, this feedback circuit is disrupted—and super‐enhancer formation prevented—by the risk variant at the lead SNP, leading to unrestrained T‐cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity. |
| format | Article |
| id | doaj-art-6f6d2d05ba2f4f178954073cc994019a |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-6f6d2d05ba2f4f178954073cc994019a2025-08-20T04:03:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-04-0112511710.15252/emmm.202012112Resolving mechanisms of immune‐mediated disease in primary CD4 T cellsChristophe Bourges0Abigail F Groff1Oliver S Burren2Chiara Gerhardinger3Kaia Mattioli4Anna Hutchinson5Theodore Hu6Tanmay Anand7Madeline W Epping8Chris Wallace9Kenneth GC Smith10John L Rinn11James C Lee12Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeDepartment of Stem Cell and Regenerative Biology, Harvard UniversityCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeDepartment of Stem Cell and Regenerative Biology, Harvard UniversityDepartment of Stem Cell and Regenerative Biology, Harvard UniversityMRC Biostatistics Unit, Cambridge Institute of Public HealthCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeDepartment of Stem Cell and Regenerative Biology, Harvard UniversityCambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of CambridgeAbstract Deriving mechanisms of immune‐mediated disease from GWAS data remains a formidable challenge, with attempts to identify causal variants being frequently hampered by strong linkage disequilibrium. To determine whether causal variants could be identified from their functional effects, we adapted a massively parallel reporter assay for use in primary CD4 T cells, the cell type whose regulatory DNA is most enriched for immune‐mediated disease SNPs. This enabled the effects of candidate SNPs to be examined in a relevant cellular context and generated testable hypotheses into disease mechanisms. To illustrate the power of this approach, we investigated a locus that has been linked to six immune‐mediated diseases but cannot be fine‐mapped. By studying the lead expression‐modulating SNP, we uncovered an NF‐κB‐driven regulatory circuit which constrains T‐cell activation through the dynamic formation of a super‐enhancer that upregulates TNFAIP3 (A20), a key NF‐κB inhibitor. In activated T cells, this feedback circuit is disrupted—and super‐enhancer formation prevented—by the risk variant at the lead SNP, leading to unrestrained T‐cell activation via a molecular mechanism that appears to broadly predispose to human autoimmunity.https://doi.org/10.15252/emmm.202012112CD4 T cellsGWASMPRAsuper‐enhancerTNFAIP3 |
| spellingShingle | Christophe Bourges Abigail F Groff Oliver S Burren Chiara Gerhardinger Kaia Mattioli Anna Hutchinson Theodore Hu Tanmay Anand Madeline W Epping Chris Wallace Kenneth GC Smith John L Rinn James C Lee Resolving mechanisms of immune‐mediated disease in primary CD4 T cells EMBO Molecular Medicine CD4 T cells GWAS MPRA super‐enhancer TNFAIP3 |
| title | Resolving mechanisms of immune‐mediated disease in primary CD4 T cells |
| title_full | Resolving mechanisms of immune‐mediated disease in primary CD4 T cells |
| title_fullStr | Resolving mechanisms of immune‐mediated disease in primary CD4 T cells |
| title_full_unstemmed | Resolving mechanisms of immune‐mediated disease in primary CD4 T cells |
| title_short | Resolving mechanisms of immune‐mediated disease in primary CD4 T cells |
| title_sort | resolving mechanisms of immune mediated disease in primary cd4 t cells |
| topic | CD4 T cells GWAS MPRA super‐enhancer TNFAIP3 |
| url | https://doi.org/10.15252/emmm.202012112 |
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