RegRegSEA: a web server for regulatory region set enrichment analysis of epigenomic data

Interpreting genome-wide epigenomic experiments, such as DNA methylation profiling and chromatin accessibility assays, requires tools that can identify which regulatory programs underlie coordinated changes across genomic regions. Without this regulatory context, lists of differential regions remain largely descriptive and difficult to interpret mechanistically. Existing approaches either apply hard significance cutoffs that discard moderate but biologically meaningful signals, or rely on gene-centric annotations that neglect enhancers and intergenic space, introducing bias into the interpretation. RegRegSEA addresses both shortcomings by adapting the Gene Set Enrichment Analysis framework directly to genomic coordinates. The server accepts a standard differential analysis table, ranks all tested intervals by a signed statistic, and computes enrichment scores against curated regulatory databases including transcription factor binding site collections. Results are returned as an interactive, publication-ready report featuring dynamic visualizations of enrichment profiles and regulatory annotations, along with downloadable leading-edge regions for downstream analyses. We demonstrate the utility of this approach through re-analysis of Down syndrome brain methylation data and chromatin accessibility in ageing mouse liver. The server is freely available at https://web.ccb.uni-saarland.de/regregsea/ and open to all users with no login required.