High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma
- Michael Johnston1,
- Ana Nikolic1,
- Nicoletta Ninkovic1,
- Paul Guilhamon2,
- Florence Cavalli3,
- Steven Seaman4,
- Franz Zemp1,
- John Lee3,
- Aly Abdelkareem1,
- Katrina Ellestad1,
- Alex Murison2,
- Michelle Kushida3,
- Fiona Coutinho3,
- Yussanne Ma5,
- Andrew Mungall5,
- Richard Moore5,
- Marco Marra5,
- Michael Taylor3,
- Peter Dirks3,
- Trevor Pugh2,
- Sorana Morrissy1,
- Bradley St Croix4,
- Douglas Mahoney1,
- Mathieu Lupien2 and
- Marco Gallo1,6
Abstract
We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including CD276. We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics datasets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
- Received November 16, 2018.
- Accepted June 26, 2019.
- Published by Cold Spring Harbor Laboratory Press
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