Top2a Differentially Modulates Promoter Activity in Embryonic Stem Cells via Trim28 Recruitment and PRC2 Displacement [ATAC-Seq]

High levels of the type II topoisomerase α (Top2a) play a crucial role in maintaining the stemness of embryonic stem cells (ESCs). However, the mechanisms governing Top2a's ESC-specific function remain largely unknown. Here, using an unbiased proteomic approach, we discovered Trim28, along with subunits of various chromatin remodeling complexes and modifiers, among the top interactors of Top2a on ESC chromatin. We demonstrate that Top2a directly interacts with Trim28 in an ESC-specific manner. Functionally, Trim28 can promote Top2a expression, and synergize with Top2a in maintaining stemness of ESCs as well as promoting induced pluripotent stem cells (iPSCs) generation. Genome-wide approaches reveal that Top2a-Trim28 co-regulated genes contribute to glycolysis and self-renewal, and Top2a fine-tunes promoter activity by recruiting Trim28 to co-activated genes and displacing PRC2 to co-repressed genes. Remarkably, targeting Top2a in combination with Trim28 in breast cancer stem cells shows an extremely synergistic anti-tumorigenic effect. Therefore, Top2a collaborates with Trim28 in ESCs to fulfill its cell type-specific functions, which may highlight the therapeutic strategy of combinational targeting of Top2a and Trim28 to combat cancer stem cells.