Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.
Autoantibodies
/ immunology
Cells, Cultured
Chromosome Mapping
/ methods
Gene Expression Profiling
/ methods
Genetic Predisposition to Disease
/ genetics
Genome-Wide Association Study
/ methods
Humans
Jurkat Cells
Lupus Erythematosus, Systemic
/ genetics
Polymorphism, Single Nucleotide
Promoter Regions, Genetic
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Proto-Oncogene Proteins c-bcl-6
/ genetics
RNA Interference
Receptors, CXCR5
/ genetics
T-Lymphocytes, Helper-Inducer
/ immunology
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
02
10
2019
accepted:
02
06
2020
entrez:
5
7
2020
pubmed:
6
7
2020
medline:
1
9
2020
Statut:
epublish
Résumé
Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.
Identifiants
pubmed: 32620744
doi: 10.1038/s41467-020-17089-5
pii: 10.1038/s41467-020-17089-5
pmc: PMC7335045
doi:
Substances chimiques
Autoantibodies
0
BCL6 protein, human
0
CXCR5 protein, human
0
Proto-Oncogene Proteins c-bcl-6
0
Receptors, CXCR5
0
HIPK1 protein, human
EC 2.7.11.1
MINK1 protein, human
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3294Subventions
Organisme : NIAID NIH HHS
ID : R01 AI146026
Pays : United States
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