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ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates

ABSTRACT: ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates

PROVIDER: PRJNA1106842 | ENA |

REPOSITORIES: ENA

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ZFTA fusion oncoproteins drive tumorigenesis through transcriptional condensates

Project description:Over 95% of ependymomas (EPNs) that arise in the cortex are driven by a gene fusion involving the zinc finger translocation associated (ZFTA) protein. Using super-resolution and lattice light sheet microscopy, we demonstrate that the most frequent fusion variant, ZFTA-RELA (ZR), forms dynamic nuclear condensates that are required for oncogene expression and tumorigenesis. Mutagenesis of ZR reveals a key intrinsically disordered region (IDR) that governs condensate formation. Condensate-modulating ZR IDR mutations impaired genomic occupancy at oncogenic loci, and inhibited the recruitment of transcriptional effector proteins, such as MED1, BRD4 and RNA polymerase II. Using nuclear magnetic resonance spectroscopy, we examined the protein structure of the critical zinc finger found in ZR, and characterized its significance for condensate formation, genomic binding, and oncogene activation. Our data leverages microscopy, genomics, cell biology, animal modeling, structural biology, and machine learning approaches to provide mechanistic insights into the processes that govern oncogene expression in ZFTA FO-driven tumors.

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TFE3 fusion oncoprotein condensates drive epigenetic reprogramming and cancer progression

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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