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

BRD4-targeting PROTAC as a unique tool to study biomolecular condensates

“…Moreover, SEs can drive the expression of specific genes, and play key roles in stem cells and cancer cells 40 . Condensates at the SEs contain many transcription factors, and co-activators such as BRD4, MED1, p300, p-TEFb, and RNA Pol II 32 , 33 , 41 , 42 . Meanwhile, we showed the interaction network of BRD4-related proteins (Fig.…”

“…To date, BRD4 is a popular anticancer drug development target, because it assembles at SEs to form condensates and plays a critical role in the regulation of oncogene expression 31 . Cancer cells utilize SEs to form condensates for regulating cell proliferation and survival through critical oncogenes 32 , 33 . The introduction of PROTAC in LLPS would allow a better understanding of the dynamic mechanism of SEs assembly and other transcriptional components to promote oncogene expression.…”

Biomolecular Liquid–Liquid Phase Separation for Biotechnology

“…For example, Saini et al recently discovered that macromolecular crowding induces LLPS, which leads to an increase in the intrinsic catalytic efficiencies of horseradish peroxidase (HRP) and glucose oxidase (GOx) [ 110 ]. Transcription factors (TFs) and RNAs also induce the formation of transcriptional condensates via LLPS, which contain clusters of multiple enhancers (super-enhancers) [ 111 ]. This phenomenon is supported by the dynamic interaction of TFs with RNA polymerase II (Pol II) clusters [ 112 ].…”

Typical Enhancers, Super-Enhancers, and Cancers

“…In principle, the anatomical patterns of enhancers’ assembly and the molecular mechanisms of their operation are exhibited on SEs structure and function, on the means of the primary DNA sequence, TF binding, and epigenetic characteristics, yet on a more extended scale. However, SEs rely on prolonged segments of the genome spanning more than 10 kb and occasionally reconstitute epigenomic landscapes of more than 100 kb length of DNA sequence [ 18 , 77 ]. These large (epi)genomic “scaffolds” demonstrate superior architecture and are composed of numerous clusters of closely spaced or overlapped enhancers’ stretches lined up in the linear dimension of the genome [ 78 ].…”

“…Thus, JQ1 reduces the occupancy of BRD4, the recruitment of MED1, and slows down the elongation of RNA pol II [ 4 , 21 , 152 , 153 ]. In addition, BRD4-targeting BET inhibitors such as BI-89499, OTX015, and CPI0610 [ 21 , 77 , 154 , 155 , 156 ] can be effectively applied against liquid and solid cancer types (e.g., neuroblastoma, medulloblastoma, acute myeloid leukemia) [ 157 , 158 , 159 ].…”