Abstract Background Mounting evidence from genome-wide studies of cancer shows that chromatin-mediated epigenetic silencing at large cohorts of genes is strongly linked to a poor prognosis. This mechanism is thought to prevent cell differentiation and enable evasion of the immune system. Drugging the cancer epigenome with small molecule inhibitors to release silenced genes from the repressed state has emerged as a powerful approach for cancer research and drug development. Targets of these inhibitors include chromatin-modifying enzymes that can acquire drug-resistant mutations. In order to directly target a generally conserved feature, elevated trimethyl-lysine 27 on histone H3 (H3K27me3), we developed the Polycomb-based Transcription Factor (PcTF), a fusion activator that targets methyl-histone marks via its N-terminal H3K27me3-binding motif, and co-regulates sets of silenced genes. Results Here, we report transcriptome profiling analyses of PcTF-treated breast cancer model cell lines. We identified a set of 19 PcTF-upregulated genes, or PUGs, that were consistent across three distinct breast cancer cell lines. These genes areÂ associated with the interferon response pathway. Conclusions Our results demonstrate for the first time a chromatin-mediated interferon-related transcriptional response driven by an engineered fusion protein that physically links repressive histone marks with active transcription.