High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma

• DOI: 10.1101/gr.246520.118
• Publication Date: 2019-06-28T00:35:40Z
• Authors: Michael J. Johnston; Ana Nikolic; Nicoletta Ninkovic; Paul Guilhamon; Florence M.G. Cav...; Steven Seaman; Franz J. Zemp; John Lee; Aly Abdelkareem; Katrina Ellestad; Alex Murison; Michelle M. Kushida; Fiona J. Coutinho; Yussanne Ma; Andrew J. Mungall; Richard Moore; Marco A. Marra; Michael D. Taylor; Peter B. Dirks; Trevor J. Pugh; Sorana Morrissy; Bradley St Croix; Douglas J. Mahoney; Mathieu Lupien; Marco Gallo
• Keywords: ChIA-PET

We investigated the role of 3D genome architecture in instructing functional properties glioblastoma stem cells (GSCs) by generating sub-5-kb resolution maps situ Hi-C. Contact at allow identification individual DNA loops, domain organization, and large-scale compartmentalization. observed differences looping architectures among GSCs from different patients, suggesting that is a further layer inter-patient heterogeneity for glioblastoma. Integration contact with chromatin transcriptional profiles identified specific mechanisms gene regulation, including convergence multiple super enhancers to stemness genes within cells. show number loops contacting correlates elevated transcription. These results indicate are hubs interaction between regulatory regions, likely ensure their sustained expression. Regions open common tested were poised expression immune-related genes, CD276 . demonstrate this co-expressed can be targeted an antibody-drug conjugate eliminate self-renewing Our integrated structural genomics data sets employed rationally identify therapeutic vulnerabilities