Abstract B045: Clustered transcription factor binding reflects transcriptional condensates at cancer super-enhancers and associates with clinical outcome

Abstract Transcriptional condensates have been shown to play a crucial role in gene regulation and dysregulation in cancer. However, genomic approaches to investigate the links between transcriptional condensates and cancer gene regulation remain underdeveloped. In this study, we employed an integrative computational framework to examine the relationships between genome-wide binding patterns of transcriptional factors (TFs) and potential transcriptional condensates at cancer super-enhancers. We found that TFs with motifs and binding patterns exhibiting a high genomic clustering tendency are significantly associated with super-enhancers. TFs with a high binding clustering tendency also possess high liquid-liquid phase separation abilities. By systematically integrating multi-omics data from TCGA samples with publicly available epigenomics data from cancer cell lines, we found that densely clustered TF binding sites, compared to non-clustered ones, are significantly more enriched at cancer super-enhancers. These clustered sites exhibit higher chromatin accessibility, increased chromatin interactions, and stronger associations with clinical outcomes in breast cancer and colon cancer. Our results suggest that the clustered genomic binding patterns and phase separation properties of TFs collectively contribute to the formation of transcriptional condensates at cancer super-enhancers. This work provides insights for identifying novel biomarkers for cancer diagnosis through biomolecular condensate-inspired genomic approaches. Citation Format: Shengyuan Wang, Zhenjia Wang, Chongzhi Zang. Clustered transcription factor binding reflects transcriptional condensates at cancer super-enhancers and associates with clinical outcome [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B045.