Deciphering Cancer-Specific H3K27ac Landscapes Through Systematic Multi-Omics Integration and Development of Open-Access Genomic Annotation Platform

H3K27ac epigenetically modulates gene expression and serves as an indicator of cancer status. Although aberrant H3K27ac has been widely studied, a comprehensive landscape of cancer-specific H3K27ac patterns remains lacking. By integrating 209 H3K27ac ChIP-seq datasets across 48 tissues and cell types, we defined 3612 universally conserved regions and a vast repertoire of cancer-specific H3K27ac alterations. Strikingly, while cancer-specific H3K27ac gains were pervasive across leukemia, hepatocellular carcinoma, breast cancer, lung adenocarcinoma, and lymphoma, losses were remarkably rare. These cancer-specific H3K27ac gains were predominantly enriched in non-coding regions, where they were associated with increased chromatin accessibility and chromatin interactions, enabling the recruitment of oncogenic transcription factors to activate target genes. Conversely, cancer-specific H3K27ac losses preferentially occurred in promoters and correlated with chromatin compaction and transcriptional repression. Mechanistic multi-omics analyses in leukemia further demonstrated this epigenetic-structural coupling. Leukemia-specific H3K27ac gains established a permissive chromatin environment that facilitated oncogenic GATA1 binding and activation of its target gene TAL1. Within this context, TAL1 exhibited increased interaction with STIL, a well-known fusion partner implicated in leukemogenesis. To enable broader application of these findings, we developed an open-access web server for genomic annotation. Collectively, our study provides a comprehensive landscape of cancer-specific H3K27ac modifications, defining them as a functional epigenetic signature of oncogenic chromatin remodeling and offering an annotation resource for understanding the regulation of the cancer genome.