PRCC-TFE3 Forms Proline-dependent Condensates and Reprograms Chromatin for tRCC Oncogenic Transcription [ATAC-seq]

Among these, the PRCC::TFE3 fusion is a prominent oncogenic driver, yet the molecular mechanisms governing its transcriptional and tumorigenic activities remain poorly defined. Here, we demonstrate that PRCC::TFE3 forms dynamic, transcriptionally active nuclear condensates that are critical for its oncogenic function.

We identify a proline-rich region within the PRCC fusion partner as the essential determinant of condensate formation. Disruption of this proline-rich region (PRW) abolishes condensate assembly, reverses fusion-driven chromatin accessibility and transcriptional reprogramming, and suppresses proliferative, migratory, and invasive phenotypes in patient-derived tRCC cell lines. Integrative RNA-seq, ATAC-seq, and CUT&RUN analyses reveal that PRCC::TFE3 condensates function as epigenetic regulatory hubs, coordinating extensive chromatin remodeling and recruitment of transcription factor networks—including TEAD-associated pathways—to amplify oncogenic programs.