A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Background:

• Single-nucleotide polymorphisms (SNPs) near the ERAP2 gene are linked to autoimmune diseases and infection outcomes.
• The functional mechanisms connecting these SNPs to ERAP2 expression and disease remain unclear due to high linkage disequilibrium.

Purpose of the Study:

• To elucidate the functional mechanisms by which SNPs regulate ERAP2 expression.
• To investigate the role of both cis-acting variants and distal regulatory elements in ERAP2 gene expression.

Main Methods:

• Reciprocal allelic replacement to assess ERAP2 expression control.
• Allele-specific conformation capture assays to identify chromatin interactions.
• SNP manipulation in the LNPEP promoter to evaluate effects on ERAP2 expression.

Main Results:

• ERAP2 expression is directly controlled by the splice region variant rs2248374.
• Disease-associated variants in the LNPEP gene promoter independently affect ERAP2 expression.
• Long-range chromatin contacts between LNPEP and ERAP2 promoters are stronger with disease-associated alleles, increasing ERAP2 expression.

Conclusions:

• Multiple SNPs cooperate to regulate ERAP2 expression, impacting autoimmune disease susceptibility.
• Disease-associated variants can transform gene promoter regions into enhancers for distal genes like ERAP2.