Aberrant CTCF binding facilitates phase-separated transcriptional condensate formation in cancer

CCCTC-binding factor (CTCF) is a transcription factor (TF) that induces DNA looping and functions as a chromatin insulator. Disruption of CTCF binding associated with DNA methylation changes have been reported in many cell systems that can result in aberrant chromatin interaction and dysregulation of gene expression. Using an integrative data science approach, we systematically analyzed hundreds of CTCF ChIP-seq datasets and other genomic big data across different human tissues and cancer samples and identified cancer-specific patterns of gained and lost CTCF binding in several cancer types. We found that cancer-specific CTCF binding events do not always arise from changes in DNA methylation or sequence mutations. Instead, CTCF binding can be recruited by clusters of transcription factor and co-factor molecules in the formation of phase-separated transcriptional condensates at super-enhancers in cancer. CTCF plays an instrumental role in maintaining the active chromatin state with the transcriptional condensates, to facilitate oncogenic transcriptional activation. This work indicates a novel function of CTCF in cancer gene expression program controlled by transcriptional condensates.