GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE344nnn/GSE344393/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE344393GEOGSEfalsePRCC-TFE3 Forms Proline-dependent Condensates and Reprograms Chromatin for tRCC Oncogenic Transcription [RNA-seq]Translocation renal cell carcinoma (tRCC) is an aggressive malignancy driven by MiT/TFE family transcription factor rearrangements, most notably TFE3 fusions. 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. Furthermore, we identify HS3ST2 and ABCB5 as novel, condensate-dependent target genes and validate them as critical mediators of tRCC progression. Our findings establish PRCC::TFE3-mediated condensate formation as a fundamental mechanism of tRCC pathogenesis and highlight condensate-dependent transcriptional networks as potential therapeutic vulnerabilities in this clinically challenging disease.2026/08/20GSE344393GSM9978344GSM9978355GSM9978343GSM9978354GSM9978346GSM9978357GSM9978356GSM9978345GSM9978348GSM9978347GSM9978349GSM9978351GSM9978350GSM9978353GSM997835234284344393Homo sapiens