Multiomic Analyses Reveal Epigenomic Alterations and New Targets of Polycomb Repressive Complex 2 in Schwann Lineage Cells and Malignant Peripheral Nerve Sheath Tumors
2024-05
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Multiomic Analyses Reveal Epigenomic Alterations and New Targets of Polycomb Repressive Complex 2 in Schwann Lineage Cells and Malignant Peripheral Nerve Sheath Tumors
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2024-05
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Malignant peripheral nerve sheath tumors (MPNST) are lethal soft tissue sarcomas occurring in 5-13% of Neurofibromatosis Type I (NF1) patients. It is thought that MPNSTs develop from benign precursors. However, the existing histologically defined stages in MPNST development need improvement. Commonly, MPNSTs harbor defects in PRC2 components EED or SUZ12, leading to loss of trimethylation of histone H3 on lysine 27 (H3K27me3), a repressive epigenetic mark. Consequently, PRC2 dysfunction may induce significant epigenomic and gene expression alterations. Our research aimed to understand mechanisms underlying benign-to-malignant tumor transformation for improved diagnosis and treatment of MPNSTs.Our first objective was to functionally validate newly defined molecular subsets of MPNSTs identified through transcriptomics and methylome analyses. Through cell line and mouse models, we confirmed these subsets are defined by enrichment of SHH and Wnt pathways. These pathways can also be therapeutically targeted with small-molecule inhibitors. The second objective focused on the role of PRC2 in gene repression, crucial for cell identity and malignant transformation. The phenotypic characterization of our novel SUZ12, NF1, and NF1+SUZ12 mutant human Schwann cell clones indicated activation of Notch and Sonic Hedgehog signaling in PRC2-deficient cells. A combination of MEK and γ-secretase inhibition showed synergy in MPNST cell lines. We identified PRC2-regulated genes and potential drivers of MPNSTs. Our identification of PRC2-regulated genes and pathways could result in more novel therapeutic approaches. In our third objective, we explored the epigenomic landscape of MPNSTs using our model human Schwann cell lines. We found major epigenomic changes in the histone code of SUZ12 mutants including complete loss of H3K27me3 with concomitant gain in H3K27 acetylation (H3K27ac). We also found that SUZ12-deficient cells become hypersensitive to histone deacetylase inhibitors. Furthermore, we found changes to chromatin organization and histone modifications with increased chromatin accessibility and developed our new hypothesis of “bivalent heterochromatin.” This comprehensive study advances our understanding of PRC2 loss in MPNSTs, utilizing engineered human Schwann cell models, established MPNST cell lines, and patient-derived xenografts. Our findings and new hypotheses offer novel insights into the genomic and epigenomic landscape of MPNSTs, paving the way for improved therapeutic strategies.
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University of Minnesota Ph.D. dissertation. May 2024. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: David Largaespada. 1 computer file (PDF); ix, 180 pages + 4 supplementary files.
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Bhunia, Minu. (2024). Multiomic Analyses Reveal Epigenomic Alterations and New Targets of Polycomb Repressive Complex 2 in Schwann Lineage Cells and Malignant Peripheral Nerve Sheath Tumors. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/264285.
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