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Resolving mechanisms of immune‐mediated disease in primary <scp>CD</scp> 4 T cells
- Source :
- EMBO Molecular Medicine, Vol 12, Iss 5, Pp n/a-n/a (2020), EMBO Molecular Medicine
- Publication Year :
- 2020
- Publisher :
- EMBO, 2020.
-
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.<br />Little progress has been made in resolving causal SNPs, genes and disease mechanisms at GWAS loci. An adapted massively‐parallel reporter assay (MPRA) allows to study immune‐mediated disease loci in CD4 T cells, the cell‐type whose regulatory DNA is most highly enriched for disease‐associated SNPs.
- Subjects :
- CD4-Positive T-Lymphocytes
0301 basic medicine
Medicine (General)
Linkage disequilibrium
Immunology
CD4 T cells
Autoimmunity
Single-nucleotide polymorphism
Genome-wide association study
Disease
Computational biology
QH426-470
Biology
medicine.disease_cause
Polymorphism, Single Nucleotide
TNFAIP3
Article
03 medical and health sciences
R5-920
0302 clinical medicine
Super-enhancer
Genetics
medicine
Humans
GWAS
SNP
NF-kappa B
Computational Biology
super‐enhancer
Articles
MPRA
030104 developmental biology
Molecular Medicine
Genetics, Gene Therapy & Genetic Disease
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 17574684 and 17574676
- Volume :
- 12
- Database :
- OpenAIRE
- Journal :
- EMBO Molecular Medicine
- Accession number :
- edsair.doi.dedup.....eedf9ad4d67e11cb433c3eac43f0b756