Super-Enhancers, Phase-Separated Condensates, and 3D Genome Organization in Cancer

SIMPLE SUMMARY: Gene expression is primarily controlled at the level of transcription, largely due to binding of transcription factors to specific sites on DNA, namely super-enhancers and promoters. Super-enhancers and enhancers can regulate distal target genes via chromatin looping mechanisms. These long-range enhancer–promoter interactions are often mediated by phase-separated condensates. In this review, we summarize recent insights into super-enhancers and phase-separated condensates and their roles in the transcriptional activation of genes involved in development and diseases such as cancer. In addition, we survey a broad array of drugs that target super-enhancers, three-dimensional genome organization, and phase-separated condensates that could be potentially used for the treatment of cancer. ABSTRACT: 3D chromatin organization plays an important role in transcription regulation and gene expression. The 3D genome is highly maintained by several architectural proteins, such as CTCF, Yin Yang 1, and cohesin complex. This structural organization brings regulatory DNA elements in close proximity to their target promoters. In this review, we discuss the 3D chromatin organization of super-enhancers and their relationship to phase-separated condensates. Super-enhancers are large clusters of DNA elements. They can physically contact with their target promoters by chromatin looping during transcription. Multiple transcription factors can bind to enhancer and promoter sequences and recruit a complex array of transcriptional co-activators and RNA polymerase II to effect transcriptional activation. Phase-separated condensates of transcription factors and transcriptional co-activators have been implicated in assembling the transcription machinery at particular enhancers. Cancer cells can hijack super-enhancers to drive oncogenic transcription to promote cell survival and proliferation. These dysregulated transcriptional programs can cause cancer cells to become highly dependent on transcriptional regulators, such as Mediator and BRD4. Moreover, the expression of oncogenes that are driven by super-enhancers is sensitive to transcriptional perturbation and often occurs in phase-separated condensates, supporting therapeutic rationales of targeting SE components, 3D genome organization, or dysregulated condensates in cancer.