Targeting the 3D genome by anthracyclines for chemotherapeutic effects

The chromatins are folded into three-dimensional (3D) structures, and aberrant chromatin 3D folding has been shown in cancer. We performed ATAC-seq and TOP2A ChIP-seq to profile the potential effects of different anthracyclines on the chromatin. We identified that unique anthracycline variants selectively target chromatin looping anchors via disrupting CTCF binding, suggesting an additional potential therapeutic effect on the 3D genome. We further performed Hi-C experiments, and data from K562 cells treated with the selective anthracycline drugs indicate that the global 3D chromatin organizations were disrupted dramatically, as exemplified by the disruption of distal regulation of the Myc gene. Furthermore, AML patients receiving anthracycline drugs showed altered chromatin structures around potential looping anchors, which linked to distinct clinical outcomes. Our data indicate that anthracyclines are potent and selective epigenomic targeting drugs and can further target the 3D genome for anticancer effects, which could be explored for personalized medicine to treat tumors with aberrant 3D chromatin structures. Overall design: CTCF ChIP-seq experiments were performed using 100,000,000 K562 cells treated with 10 µM aclarubicin or daunrubicin for 4 hours.