2024/12/27 by Jing Wan, Antoinette van Ouwerkerk, Jean-Christophe Mouren +5 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · #Epigenetics and DNA Methylation #Genetic Associations and Epidemiology #Genomics and Chromatin Dynamics
paper · pdf · doi:10.1093/nar/gkae1270
openalex publication_date 2024/12/27 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
There is growing evidence that a wide range of human diseases and physiological traits are influenced by genetic variation of cis-regulatory elements. We and others have shown that a subset of promoter elements, termed Epromoters, also function as enhancer regulators of distal genes. This opens a paradigm in the study of regulatory variants, as single nucleotide polymorphisms (SNPs) within Epromoters might influence the expression of several (distal) genes at the same time, which could disentangle the identification of disease-associated genes. Here, we built a comprehensive resource of human Epromoters using newly generated and publicly available high-throughput reporter assays. We showed that Epromoters display intrinsic and epigenetic features that distinguish them from typical promoters. By integrating Genome-Wide Association Studies (GWAS), expression Quantitative Trait Loci (eQTLs) and 3D chromatin interactions, we found that regulatory variants at Epromoters are concurrently associated with more disease and physiological traits, as compared with typical promoters. To dissect the regulatory impact of Epromoter variants, we evaluated their impact on regulatory activity by analyzing allelic-specific high-throughput reporter assays and provided reliable examples of pleiotropic Epromoters. In summary, our study represents a comprehensive resource of regulatory variants supporting the pleiotropic role of Epromoters.