Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity

Rajendran Sanalkumar, Rui Dong, Lukuo Lee, Yu Hang Xing, Sowmya Iyer, Igor Letovanec, Stefano La Rosa, Giovanna Finzi, Elettra Musolino, Roberto Papait, Ivan Chebib, G. Petur Nielsen, Raffaele Renella, Gregory M. Cote, Edwin Choy, Martin Aryee, Kimberly Stegmaier, Ivan Stamenkovic, Miguel N. Rivera, Nicolò Riggi

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Cell fate transitions observed in embryonic development involve changes in three-dimensional genomic organization that provide proper lineage specification. Whether similar events occur within tumor cells and contribute to cancer evolution remains largely unexplored. We modeled this process in the pediatric cancer Ewing sarcoma and investigated high-resolution looping and large-scale nuclear conformation changes associated with the oncogenic fusion protein EWS-FLI1. We show that chromatin interactions in tumor cells are dominated by highly connected looping hubs centered on EWS-FLI1 binding sites, which directly control the activity of linked enhancers and promoters to establish oncogenic expression programs. Conversely, EWS-FLI1 depletion led to the disassembly of these looping networks and a widespread nuclear reorganization through the establishment of new looping patterns and large-scale compartment configuration matching those observed in mesenchymal stem cells, a candidate Ewing sarcoma progenitor. Our data demonstrate that major architectural features of nuclear organization in cancer cells can depend on single oncogenes and are readily reversed to reestablish latent differentiation programs.

Original languageEnglish
Article numbereabo3789
JournalScience advances
Volume9
Issue number13
DOIs
StatePublished - Mar 2023
Externally publishedYes

Fingerprint

Dive into the research topics of 'Highly connected 3D chromatin networks established by an oncogenic fusion protein shape tumor cell identity'. Together they form a unique fingerprint.

Cite this