Tang Seng Chuan, Vijayakumar Udhaya, Zhang Ying, Fullwood Melissa Jane
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Cancers (Basel). 2022 Jun 10;14(12):2866. doi: 10.3390/cancers14122866.
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.
三维染色质组织在转录调控和基因表达中发挥着重要作用。三维基因组由几种结构蛋白高度维持，如CTCF、阴阳1和黏连蛋白复合体。这种结构组织使调控性DNA元件与其靶启动子紧密相邻。在本综述中，我们讨论了超级增强子的三维染色质组织及其与相分离凝聚物的关系。超级增强子是DNA元件的大簇。它们在转录过程中可通过染色质环化与靶启动子发生物理接触。多种转录因子可结合增强子和启动子序列，并募集一系列复杂的转录共激活因子和RNA聚合酶II以实现转录激活。转录因子和转录共激活因子的相分离凝聚物与在特定增强子处组装转录机器有关。癌细胞可劫持超级增强子来驱动致癌转录，以促进细胞存活和增殖。这些失调的转录程序可导致癌细胞高度依赖转录调节因子，如中介体和BRD4。此外，由超级增强子驱动的癌基因表达对转录扰动敏感，且常发生在相分离凝聚物中，这支持了靶向癌症中超级增强子成分、三维基因组组织或失调凝聚物的治疗原理。
