Gene regulatory networks are pivotal for many biological processes. In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc. The Polycomb module represses developmental genes, while the Myc module is associated with proliferative functions, and its mis-regulation is linked to cancer development. New work from the Shi lab, published in Molecular Cell (see also the Preview in the same issue), showed that, in mESCs, the Polycomb repressive complex 2 (PRC2)-associated protein EPOP/C17orf96 co-localizes at chromatin with members of the Myc and Polycomb module. EPOP interacts with the transcription elongation factor Elongin BC and the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC. EPOP is commonly upregulated in human cancer, and its loss impairs the proliferation of several human cancer cell lines. These findings establish EPOP as a transcriptional modulator, which impacts both Polycomb and active gene transcription in mammalian cells, and a possible involvement of EPOP in human cancerogenesis.