Unraveling an enhancer-silencer regulatory element showing epistatic interaction with a variant that escaped genome-wide association studies
A dual-function cis-regulatory element (“ESpromoter”) can act as both enhancer and silencer to tune ATP2B4 and LAX1 in human T cells; its allele-specific interaction with rs11240391 helps explain severe malaria risk.
Abstract (concise summary)
The authors identify an enhancer–silencer promoter (ESpromoter) that activates ATP2B4 yet represses LAX1 in single human T cells. Using integrative genomics, CRISPR perturbations, reporter assays, and cohort genetics, they show an epistatic interaction between five ESpromoter SNPs and rs11240391 in the LAX1 promoter. This allele-specific interaction reduces LAX1 expression and associates with severe malaria susceptibility, challenging the classic enhancer–silencer dichotomy.
Key takeaways
- Dual-function regulatory DNA: one element can enhance one gene (ATP2B4) while silencing another (LAX1) within the same cell context.
- Mechanistic link: the LAX1 promoter variant rs11240391 (FOS::JUN binding site) modifies the repression strength exerted by the ESpromoter.
- Evidence stack: chromatin interaction maps, CRISPR deletions, RT-qPCR, luciferase reporters, and human cohort genetics support the model.
- Disease relevance: allele-specific regulation contributes to severe malaria risk via T-cell activation pathways.
Citation
Adjemout M, Nisar S, Escandell A, et al. Unraveling an enhancer-silencer regulatory element showing epistatic interaction with a variant that escaped genome-wide association studies. Cell Genomics. 2025;5(7):100889. doi:10.1016/j.xgen.2025.100889.
Note: This post contains a paraphrased summary and metadata only. For the official full text and figures, visit the PMC link above.