TAD Variance Promotes Cancer Driver Genes through Redistribution of Super-Enhancers

Three-dimensional (3D) genome is closely associated with cell fate. However, the 3D genome alteration and the transcriptionally regulatory mechanism in cancer development is not fully understand. Here, we employed in situ HiC to show the marked alteration of 3D chromatin structure during normal to tumor transfer. Meanwhile, we identified super-enhancer (SE) in colorectal cancer (CRC) HCT116 cell line. As opposite to the modest effect of compartment switch on the activation of SEs and SE-related genes, TAD variance largely contributes to their activation. Moreover, 35 SE-related oncogenic candidates were identified by overlapping the SE-related genes with super-higher expressed genes in HCT116. Knockdown of two representative candidates, PDP1 or RPS2, significantly suppressed HCT116 cell growth and migration while induced cell apoptosis, indicating the accuracy of SE-dependent identification method. Furthermore, interchromosomal translocation also contributes to TAD variance and the activation of PDP1 and RPS2 by clustering SEs. Taken together, our results illuminate the mechanism how 3D genome alteration during normal to tumor transition regulates SE-related oncogenic genes in CRC.