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TFE3 fusion oncoprotein condensates drive epigenetic reprogramming and cancer progression

ABSTRACT: Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. This cancer is primarily driven by fusion oncoproteins (FOs) arising from chromosomal rearrangements, yet their role in oncogenesis remains incompletely understood. Here we investigate TFE3 fusion in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3, constituting 30-40% of all TFE3 FOs. We find that TFE3 FOs form liquid-like condensates with heightened transcriptional activity, selectively recruiting active transcription markers to TFE3 target genes and promoting cell proliferation, migration, and drug resistance. The coiled-coil domains (CCD) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. We comprehensively investigated the genome-wide recruitment of TFE3 FOs and their CCD-altered variants, uncovering widespread changes in chromatin accessibility and genomic binding specifically at TFE3 and AP-1 regulated loci. We also observe altered H3K27ac deposition at enhancers and super-enhancers notably at pro-growth and stemness markers such as BCL2 and CD44, and identify novel oncogenic target genes of TFE3 FOs. Disruption of condensate formation, resulting from CCD domain alterations in FOs, robustly dysregulates their role in chromatin accessibility, chromatin binding, H3K27ac occupancy, and gene expression. Altogether our integrated analyses underscore the critical functions of TFE3 FO condensates in driving RCC progression, offering pivotal insights for future targeted therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281477 | GEO | 2025/04/02

REPOSITORIES: GEO

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TFE3 fusion oncoprotein condensates drive epigenetic reprogramming and cancer progression [CUT&RUN]

Project description:Translocation renal cell carcinoma (tRCC) presents a significant clinical challenge due to its aggressiveness and limited treatment options. This cancer is primarily driven by fusion oncoproteins (FOs) arising from chromosomal rearrangements, yet their role in oncogenesis remains incompletely understood. Here we investigate TFE3 fusion in tRCC, focusing on NONO::TFE3 and SFPQ::TFE3, constituting 30-40% of all TFE3 FOs. We find that TFE3 FOs form liquid-like condensates with heightened transcriptional activity, selectively recruiting active transcription markers to TFE3 target genes and promoting cell proliferation, migration, and drug resistance. The coiled-coil domains (CCD) of NONO and SFPQ are essential for condensate formation, prolonging TFE3 FOs' chromatin binding time and enhancing transcription. We comprehensively investigated the genome-wide recruitment of TFE3 FOs and their CCD-altered variants, uncovering widespread changes in chromatin accessibility and genomic binding specifically at TFE3 and AP-1 regulated loci. We also observe altered H3K27ac deposition at enhancers and super-enhancers notably at pro-growth and stemness markers such as BCL2 and CD44, and identify novel oncogenic target genes of TFE3 FOs. Disruption of condensate formation, resulting from CCD domain alterations in FOs, robustly dysregulates their role in chromatin accessibility, chromatin binding, H3K27ac occupancy, and gene expression. Altogether our integrated analyses underscore the critical functions of TFE3 FO condensates in driving RCC progression, offering pivotal insights for future targeted therapeutic strategies.

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Shared sequence features of diverse oncofusions promote gain-of-function RNA Pol II partitioning to drive gene activation

Project description:Translocation renal cell carcinoma is a rare but aggressive cancer driven by oncogenic fusions between the DNA-binding transcription factor TFE3 and diverse subunits. We have found that these diverse fusions promote condensate formation and activation of target genes. To investigate what the condensates formed by different TFE3 fusions partition we used a cell-free method relying on condensate reconstitution within a nuclear extract. Using recombinant purified PRCC-TFE3 or ASPL-TFE3, we reconstituted condensates in a soluble nuclear extract. The extract was then fractionated by centrifugation into a supernatant and pellet. For each fusion supernatant and pellet fractions were collected in triplicate. Samples were individually labeled using a 6-plex tandem mass tag (TMT) post-tryptic isobaric labeling strategy and the three supernatant and three pellet fractions of each fusion were mixed and analyzed by LC-MS to provide quantitative measurements of partitioning. In summary, we deposit 2 TMT 6-plex samples which represent triplicates for each PRCC-TFE3 (1071162 F1-8) and ASPL-TFE3 (1069084 F1-8). TMT labels 126, 127, 128: Sup TMT labels 129, 130, 131: Pellet

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DETECTION OF FOUR NOVEL RENAL TUMORS CASES HARBORING RBM10-TFE3 FUSIONS

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