In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma
Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2017.
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| Other Authors: | |
| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2017
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| Online Access: | http://hdl.handle.net/1721.1/111285 |
| _version_ | 1811089577806397440 |
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| author | Stanciu, Monica |
| author2 | Jacqueline Lees. |
| author_facet | Jacqueline Lees. Stanciu, Monica |
| author_sort | Stanciu, Monica |
| collection | MIT |
| description | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2017. |
| first_indexed | 2024-09-23T14:21:25Z |
| format | Thesis |
| id | mit-1721.1/111285 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T14:21:25Z |
| publishDate | 2017 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1112852022-07-09T07:42:09Z In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma Stanciu, Monica Jacqueline Lees. Massachusetts Institute of Technology. Department of Biology. Massachusetts Institute of Technology. Department of Biology Biology. Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2017. Cataloged from PDF version of thesis. Page 158 blank. Includes bibliographical references (pages 125-157). Glioblastoma (GBM), the most prevalent primary brain tumor in adults, remains a largely intractable malignancy that carries an extremely poor prognosis. Large scale genomic analyses have greatly expanded our knowledge of the genomic landscape of GBM. Recently, we have also begun to gain an appreciation for how dysregulation of epigenetic control can contribute to gliomagenesis. To expand our understanding of the roles of epigenetic mediators in GBM, we establish an orthotopic transplantation model and demonstrate its feasibility for in vivo shRNA screening. We describe the results of parallel in vivo and in vitro shRNA screens to uncover epigenetic regulators with oncogenic functions and chemosensitizing potential in GBM. From these screens, the protein arginine methyltransferase PRMT5 emerges as an important mediator of GBM tumor growth in the presence and absence of chemotherapy. We demonstrate that PRMT5 loss impairs cellular fitness in vitro and this effect is dependent on its methyltransferase activity. Furthermore, in vivo transplantation of both murine and human GBM cells shows that PRMT5 knockdown impairs tumor growth and leads to a survival benefit. Building on these observations, we report the first use of a highly selective PRMT5 inhibitor in extending survival in a GBM xenograft model. We also describe the results of initial in vitro and in vivo experiments combining PRMT5 genetic depletion or pharmacological inhibition with chemotherapy. To gain a better understanding of the effects of PRMT5 inhibition, we perform gene expression analysis, and find a putative role for PRMT5 in maintaining GBM cell identity. Importantly, we observe that PRMT5 impacts gene expression by regulating RNA splicing to exert specific control over a recently described class of intronic sequences known as detained introns. Together, the results presented here highlight a key role for PRMT5 in GBM and suggest that it represents a viable target for therapeutic intervention in this intractable disease. by Monica Stanciu. Ph. D. 2017-09-15T15:27:26Z 2017-09-15T15:27:26Z 2017 2017 Thesis http://hdl.handle.net/1721.1/111285 1002420083 eng MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 158 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Biology. Stanciu, Monica In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title | In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title_full | In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title_fullStr | In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title_full_unstemmed | In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title_short | In vivo shRNA screen reveals PRMT5 as a key regulator in glioblastoma |
| title_sort | in vivo shrna screen reveals prmt5 as a key regulator in glioblastoma |
| topic | Biology. |
| url | http://hdl.handle.net/1721.1/111285 |
| work_keys_str_mv | AT stanciumonica invivoshrnascreenrevealsprmt5asakeyregulatoringlioblastoma |