3D genome mapping identifies subgroup-specific chromosome conformations and tumor-dependency genes in ependymoma

Konstantin Okonechnikov, Aylin Camgöz, Owen Chapman, Sameena Wani, Donglim Esther Park, Jens-Martin Hübner, Abhijit Chakraborty, Meghana Pagadala, Rosalind Bump, Sahaana Chandran, Katerina Kraft, Rocio Acuna-Hidalgo, Derek Reid, Kristin Sikkink, Monika Mauermann, Edwin F. Juarez, Anne Jenseit, James T. Robinson, Kristian W. Pajtler, Till Milde, Natalie Jäger, Petra Fiesel, Ling Morgan, Sunita Sridhar, Nicole G. Coufal, Michael Levy, Denise Malicki, Charlotte Hobbs, Stephen Kingsmore, Shareef Nahas, Matija Snuderl, John Crawford, Robert J. Wechsler-Reya, Tom Belle Davidson, Jennifer Cotter, George Michaiel, Gudrun Fleischhack, Stefan Mundlos, Anthony Schmitt, Hannah Carter, Kulandaimanuvel Antony Michealraj, Sachin A. Kumar, Michael D. Taylor, Jeremy Rich, Frank Buchholz, Jill P. Mesirov, Stefan M. Pfister, Ferhat Ay, Jesse R. Dixon, Marcel Kool and Lukas Chavez ()
Additional contact information
Konstantin Okonechnikov: Hopp Children’s Cancer Center (KiTZ)
Aylin Camgöz: Hopp Children’s Cancer Center (KiTZ)
Owen Chapman: University of California San Diego (UCSD)
Sameena Wani: University of California San Diego (UCSD)
Donglim Esther Park: University of California, San Diego
Jens-Martin Hübner: Hopp Children’s Cancer Center (KiTZ)
Abhijit Chakraborty: La Jolla Institute for Immunology
Meghana Pagadala: University of California San Diego (UCSD)
Rosalind Bump: Salk Institute for Biological Studies
Sahaana Chandran: Salk Institute for Biological Studies
Katerina Kraft: Stanford University
Rocio Acuna-Hidalgo: Max Planck Institute for Molecular Genetics
Derek Reid: Arima Genomics, Inc
Kristin Sikkink: Arima Genomics, Inc
Monika Mauermann: Hopp Children’s Cancer Center (KiTZ)
Edwin F. Juarez: University of California San Diego (UCSD)
Anne Jenseit: Hopp Children’s Cancer Center (KiTZ)
James T. Robinson: University of California San Diego (UCSD)
Kristian W. Pajtler: Hopp Children’s Cancer Center (KiTZ)
Till Milde: Hopp Children’s Cancer Center (KiTZ)
Natalie Jäger: Hopp Children’s Cancer Center (KiTZ)
Petra Fiesel: Hopp Children’s Cancer Center (KiTZ)
Ling Morgan: University of California San Diego (UCSD)
Sunita Sridhar: University of California San Diego (UCSD)
Nicole G. Coufal: 2880 Torrey Pines Scenic Drive
Michael Levy: University of California San Diego – Rady Children’s Hospital
Denise Malicki: University of California San Diego – Rady Children’s Hospital
Charlotte Hobbs: Rady Children’s Institute for Genomic Medicine
Stephen Kingsmore: Rady Children’s Institute for Genomic Medicine
Shareef Nahas: Rady Children’s Institute for Genomic Medicine
Matija Snuderl: NYU Grossman School of Medicine
John Crawford: University of California San Diego – Rady Children’s Hospital
Robert J. Wechsler-Reya: 2880 Torrey Pines Scenic Drive
Tom Belle Davidson: Children’s Hospital Los Angeles
Jennifer Cotter: Children’s Hospital Los Angeles
George Michaiel: Children’s Hospital Los Angeles
Gudrun Fleischhack: University Hospital Essen
Stefan Mundlos: Max Planck Institute for Molecular Genetics
Anthony Schmitt: Arima Genomics, Inc
Hannah Carter: University of California San Diego (UCSD)
Kulandaimanuvel Antony Michealraj: University of Toronto
Sachin A. Kumar: University of Toronto
Michael D. Taylor: University of Toronto
Jeremy Rich: University of California, San Diego
Frank Buchholz: Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR)
Jill P. Mesirov: University of California San Diego (UCSD)
Stefan M. Pfister: Hopp Children’s Cancer Center (KiTZ)
Ferhat Ay: La Jolla Institute for Immunology
Jesse R. Dixon: Salk Institute for Biological Studies
Marcel Kool: Hopp Children’s Cancer Center (KiTZ)
Lukas Chavez: University of California San Diego (UCSD)

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Ependymoma is a tumor of the brain or spinal cord. The two most common and aggressive molecular groups of ependymoma are the supratentorial ZFTA-fusion associated and the posterior fossa ependymoma group A. In both groups, tumors occur mainly in young children and frequently recur after treatment. Although molecular mechanisms underlying these diseases have recently been uncovered, they remain difficult to target and innovative therapeutic approaches are urgently needed. Here, we use genome-wide chromosome conformation capture (Hi-C), complemented with CTCF and H3K27ac ChIP-seq, as well as gene expression and DNA methylation analysis in primary and relapsed ependymoma tumors, to identify chromosomal conformations and regulatory mechanisms associated with aberrant gene expression. In particular, we observe the formation of new topologically associating domains (‘neo-TADs’) caused by structural variants, group-specific 3D chromatin loops, and the replacement of CTCF insulators by DNA hyper-methylation. Through inhibition experiments, we validate that genes implicated by these 3D genome conformations are essential for the survival of patient-derived ependymoma models in a group-specific manner. Thus, this study extends our ability to reveal tumor-dependency genes by 3D genome conformations even in tumors that lack targetable genetic alterations.

Date: 2023
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DOI: 10.1038/s41467-023-38044-0

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