Pan-cancer silencer transcription atlas reveals leukemia silencer hijacking FOXP1 to enhance MYC oncogene

Abstract Numerous non-coding regulatory elements have been identified in the human genome. However, our understanding of silencers remains largely incomplete. Here, we proposed the concept of silencer transcriptional activity (STA) to investigated silencers from a new perspective using >20,000 transcriptomes. We demonstrated that lower STAs predicted better patient outcomes in most cancers, and a subset of STAs distinguished tumors from noncancerous tissues for most cancer types. Importantly, we discovered a silencer-linked RNA (slRNA) of a leukemia cell-specific silencer (LeSSi). Knocking down (KD) of the slRNA significantly decreased leukemia cell viability and migration and increased cellular apoptosis. Furthermore, the direct link and functional similarity between LeSSi and slRNA were established by CRISPR/Cas9 knocking out (KO) of LeSSi. Mechanistically, the slRNA hijacked FOXP1, which functions here both as a known transcription factor (TF), and more importantly, as a novel RNA binding protein (RBP), thereby preventing FOXP1 from binding to the promoter of proto-oncogene MYC and subsequently promoting MYC transcription. Collectively, our work provides insights into the functions of silencers in cancer and identified a slRNA hijacking FOXP1 to enhance MYC expression in leukemia cells.