@article{Johnston27062019,
author = {Johnston, Michael and Nikolic, Ana and Ninkovic, Nicoletta and Guilhamon, Paul and Cavalli, Florence and Seaman, Steven and Zemp, Franz and Lee, John and Abdelkareem, Aly and Ellestad, Katrina and Murison, Alex and Kushida, Michelle and Coutinho, Fiona and Ma, Yussanne and Mungall, Andrew and Moore, Richard and Marra, Marco and Taylor, Michael and Dirks, Peter and Pugh, Trevor and Morrissy, Sorana and St Croix, Bradley and Mahoney, Douglas and Lupien, Mathieu and Gallo, Marco}, 
title = {High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma},
year = {2019}, 
doi = {10.1101/gr.246520.118}, 
elocation-id = {gr.246520.118}, 
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.}, 
URL = {http://genome.cshlp.org/content/early/2019/06/27/gr.246520.118.abstract}, 
eprint = {http://genome.cshlp.org/content/early/2019/06/27/gr.246520.118.full.pdf+html}, 
journal = {Genome Research} 
}