Interestingly, in T-cell acute lymphoblastic leukemia (T-ALL), short-term Notch inhibition only diminishes MYC enhancer activity but not looping to the promoter, suggesting that Notch mediates chromatin loops in a lineage- and locus-specific manner. By subjecting triple-negative breast cancer and mantle cell lymphoma cells to short-term Notch inhibition and reactivation, I discovered that beyond its known role in activating distal enhancers, Notch can dynamically reposition distal enhancers to the promoters of pro-survival genes such as MYC but has limited impact on higher-order chromatin structures including topologically associated domains (TADs) and compartments. ![]() Here, I used three cancer types with oncogenic mutations in the signaling-dependent developmental transcription factor NOTCH1 as models to probe the contributions of genome misfolding to oncogenesis and anti-cancer therapy resistance. Moreover, besides a few architectural proteins, the roles of other transcription factors in chromatin topology remain elusive. However, the mechanisms of the establishment and maintenance of genome folding and the implications of their disruption in cancer are largely unexplored. Recent advances in chromatin conformation capture techniques coupled with high-throughput sequencing and fluorescence in situ hybridization combined with high-content microscopy greatly advanced the mapping of 3D genome at kilo-base resolutions. ![]() Compared to the understanding of cis-regulatory elements on the linear chromatin, our knowledge about the three-dimensional (3D) organization of the human genome is still limited. Spatiotemporal regulation of gene expression governs cellular development and malignant transformation.
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