Abstract PR09: STAG2 mutations alter topologic organization of the genome and cis-mediated interactions
2020
STAG2 is one of the most recurrently mutated genes in human cancer, including in Ewing sarcoma, an aggressive bone tumor driven by the chimeric EWSR1-FLI1 transcription factor. We and others have shown that STAG2 mutations occurs in approximately 20% of Ewing sarcoma, leading most frequently to complete loss of function (LOF) of its protein. We also showed that STAG2 mutations were associated with poor outcome for these patients. However, functional mechanisms associated with these mutations are still poorly understood. STAG2 encodes an integral member of the cohesin complex, a ring-shaped multiprotein structure, which is important for proper sister chromatid cohesion and release during mitosis. Cohesin, together with CTCF, is also essential to shape the architecture of the genome through its ring structure that allows for chromatin loops formation. Here, we investigated STAG2 and STAG1 functions using isogenic proficient and deficient Ewing sarcoma models. Using extensive characterization of these models by transcriptomics and epigenetics approaches, we demonstrate that STAG2 LOF has a major impact on the expression of genes associated with enhancer features, highlighting STAG2 and EWSR1-FLI1 convergent effects. Using chromatin conformation capture methods, we further show that this transcriptomic modulation results from a STAG2 LOF specific topologic alteration of the genome. This work therefore unravels a new fundamental role of STAG2 in topologic organization of the genome and in gene regulation. This abstract is also being presented as Poster B53. Citation Format: Didier Surdez, Sakina Zaidi, Sandrine Grossetete, Virginie Raynal, Sylvain Baulande, Veronique Hill, Olivier Delattre. STAG2 mutations alter topologic organization of the genome and cis-mediated interactions [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr PR09.
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