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A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs
- Source :
- Cell Genomics, Vol 4, Iss 1, Pp 100460- (2024)
- Publication Year :
- 2024
- Publisher :
- Elsevier, 2024.
-
Abstract
- Summary: Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are associated with various autoimmune conditions, as well as protection against lethal infections. Due to high linkage disequilibrium, numerous trait-associated SNPs are correlated with ERAP2 expression; however, their functional mechanisms remain unidentified. We show by reciprocal allelic replacement that ERAP2 expression is directly controlled by the splice region variant rs2248374. However, disease-associated variants in the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the gene promoters of LNPEP and ERAP2 and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. These findings show that multiple SNPs act in concert to regulate ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.
- Subjects :
- ERAP2
GWAS
autoimmunity
SNP
eQTL
rs2248374
Genetics
QH426-470
Internal medicine
RC31-1245
Subjects
Details
- Language :
- English
- ISSN :
- 2666979X
- Volume :
- 4
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Cell Genomics
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.f5055cff96b4f289ee5f7103baea2ba
- Document Type :
- article
- Full Text :
- https://doi.org/10.1016/j.xgen.2023.100460