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High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma

  1. Author:
    Johnston, Michael J.
    Nikolic, Ana
    Ninkovic, Nicoletta
    Guilhamon, Paul
    Cavalli, Florence M. G.
    Seaman,Steven
    Zemp, Franz J.
    Lee, John
    Abdelkareem, Aly
    Ellestad, Katrina
    Murison, Alex
    Kushida, Michelle M.
    Coutinho, Fiona J.
    Ma, Yussanne
    Mungall, Andrew J.
    Moore, Richard
    Marra, Marco A.
    Taylor, Michael D.
    Dirks, Peter B.
    Pugh, Trevor J.
    Morrissy, Sorana
    St Croix,Brad
    Mahoney, Douglas J.
    Lupien, Mathieu
    Gallo, Marco

  2. Author Address

    Univ Calgary, Charbonneau Canc Inst, Clark Smith Brain Tumour Ctr, Calgary, AB T2N 4N1, Canada.Univ Calgary, Alberta Childrens Hosp Res Inst, Calgary, AB T2N 4N1, Canada.Univ Calgary, Cumming Sch Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada.Univ Toronto, Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada.Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 0A4, Canada.NCI, Tumor Angiogenesis Unit, MCGP, NIH, Frederick, MD 21702 USA.BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC VSZ 4S6, Canada.Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada.Univ Calgary, Cumming Sch Med, Dept Microbiol Immunol & Infect Dis, Calgary, AB T2N 4N1, Canada.Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1A8, Canada.Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada.Univ Calgary, Cumming Sch Med, Dept Physiol & Pharmacol, Calgary, AB T2N 4N1, Canada.
    1. Year: 2019
    2. Date: AUG
  2. Journal: GENOME RESEARCH
  3. COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT,
    1. 29
    2. 8
    3. Pages: 1211-1222
  5. Type of Article: Article
  6. ISSN: 1088-9051
  1. 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 data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.

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External Sources

  1. View Full Text
  2. DOI: 10.1101/gr.246520.118
  3. PMID: 31249064
  4. PMCID: PMC6673710
  5. View record in Web of Science®
  6. WOS: 000482830700001

Library Notes

  1. Fiscal Year: FY2018-2019
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