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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Konstantin Okonechnikov - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Aylin Camgöz - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Owen Chapman - , University of California at San Diego (Author)
  • Sameena Wani - , University of California at San Diego (Author)
  • Donglim Esther Park - , University of California at Irvine (Author)
  • Jens-Martin Hübner - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Abhijit Chakraborty - , La Jolla Institute for Allergy and Immunology (Author)
  • Meghana Pagadala - , University of California at San Diego (Author)
  • Rosalind Bump - , Salk Institute for Biological Studies (Author)
  • Sahaana Chandran - , Salk Institute for Biological Studies (Author)
  • Katerina Kraft - , Stanford University (Author)
  • Rocio Acuna-Hidalgo - , Max Planck Institute for Molecular Genetics (Author)
  • Derek Reid - , Arima Genomics (Author)
  • Kristin Sikkink - , Arima Genomics (Author)
  • Monika Mauermann - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Edwin F Juarez - , University of California at San Diego (Author)
  • Anne Jenseit - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • James T Robinson - , University of California at San Diego (Author)
  • Kristian W Pajtler - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Till Milde - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Natalie Jäger - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Petra Fiesel - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Ling Morgan - , University of California at San Diego (Author)
  • Sunita Sridhar - , University of California at San Diego (Author)
  • Nicole G Coufal - , Sanford Consortium for Regenerative Medicine (Author)
  • Michael Levy - , Rady Children's Hospital (Author)
  • Denise Malicki - , Rady Children's Hospital (Author)
  • Charlotte Hobbs - , Rady Children's Institute for Genomic Medicine (Author)
  • Stephen Kingsmore - , Rady Children's Institute for Genomic Medicine (Author)
  • Shareef Nahas - , Rady Children's Institute for Genomic Medicine (Author)
  • Matija Snuderl - , NYU Grossman School of Medicine (Author)
  • John Crawford - , Rady Children's Hospital (Author)
  • Robert J Wechsler-Reya - , Sanford Consortium for Regenerative Medicine (Author)
  • Tom Belle Davidson - , Children’s Hospital Los Angeles (Author)
  • Jennifer Cotter - , Children’s Hospital Los Angeles (Author)
  • George Michaiel - , Children’s Hospital Los Angeles (Author)
  • Gudrun Fleischhack - , University Hospital Essen (Author)
  • Stefan Mundlos - , Max Planck Institute for Molecular Genetics (Author)
  • Anthony Schmitt - , Arima Genomics (Author)
  • Hannah Carter - , University of California at San Diego (Author)
  • Kulandaimanuvel Antony Michealraj - , University of Toronto (Author)
  • Sachin A Kumar - , University of Toronto (Author)
  • Michael D Taylor - , University of Toronto (Author)
  • Jeremy Rich - , University of California at Irvine (Author)
  • Frank Buchholz - , Chair of Medical Systems Biology, University Cancer Centre, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Carl Gustav Carus Dresden, German Cancer Research Center (DKFZ) (Author)
  • Jill P Mesirov - , University of California at San Diego (Author)
  • Stefan M Pfister - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Ferhat Ay - , La Jolla Institute for Allergy and Immunology (Author)
  • Jesse R Dixon - , Salk Institute for Biological Studies (Author)
  • Marcel Kool - , Hopp Children's Cancer Center Heidelberg (KiTZ) (Author)
  • Lukas Chavez - , University of California at San Diego (Author)

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.

Details

Original languageEnglish
Article number2300
Number of pages1
JournalNature communications
Volume14
Issue number1
Publication statusPublished - 21 Apr 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10121654
Scopus 85153555253

Keywords

Keywords

  • Child, Humans, Child, Preschool, Neoplasm Recurrence, Local/genetics, Chromosomes, Chromosome Mapping, Ependymoma/genetics, Genome, Chromatin/genetics

Library keywords