Spatially clustered pattern of transcription factor binding reveals phase-separated transcriptional condensates at super-enhancers

ABSTRACT Many transcription factors (TFs) have been shown to bind at super-enhancers, forming transcriptional condensates to activate transcription in many cellular systems. Genomic and epigenomic determinants of phase-separated transcriptional condensates are not well understood. Here we systematically analyzed DNA sequence motifs and TF binding profiles across human cell types to identify the molecular features that contribute to the formation of transcriptional condensates. We found that most DNA sequence motifs are not distributed randomly in the genome, but exhibiting spatially clustered patterns associated with super-enhancers. TF binding sites are further clustered and enriched at cell-type-specific super-enhancers. TFs exhibiting clustered binding patterns also have high liquid-liquid phase separation abilities. Compared to regular TF binding, densely clustered TF binding sites are more enriched at cell-type-specific super-enhancers with higher chromatin accessibility, higher chromatin interaction, and higher association with cancer outcome. Our results indicate that the clustered pattern of genomic binding and the phase separation properties of TFs collectively contribute to the formation of transcriptional condensates.