CpG islands are topological sinks for transcription-induced DNA supercoiling

Transcription-induced DNA supercoiling is relaxed by topoisomerases, yet negative supercoiling accumulates at active gene promoters. How promoter sequences and chromatin architecture organise and regulate this torsional stress remains poorly understood. Using Twist-seq, a genome-wide assay for DNA supercoiling, we show that highly transcribed CpG island (CGI) promoters accumulate elevated levels of negative supercoiling compared to highly transcribed non-CGI promoters. Coarse-grained molecular dynamics simulations predict that the capacity of CGI promoters to accommodate elevated negative supercoiling arises from the intrinsic physical properties of CGI DNA. CGI sequence and local chromatin architecture favour localised melting at AT-rich pockets and DNA writhe within promoter-proximal nucleosome-free regions, providing an energetically favourable mechanism to dissipate torsional stress. Consistently, CGI promoters show a depletion in Top1 and increased ssDNA in vivo. We propose that CGIs function as sequence-encoded topological sinks that buffer transcription-induced torsional stress, with increased somatic mutation rates at highly expressed CGI promoters suggesting a potential genome-stability cost.