EWSR1-ATF1 dependent 3D connectivity regulates oncogenic and differentiation programs in Clear Cell Sarcoma.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 04 2022
27 04 2022
Historique:
received:
03
08
2021
accepted:
07
04
2022
entrez:
28
4
2022
pubmed:
29
4
2022
medline:
30
4
2022
Statut:
epublish
Résumé
Oncogenic fusion proteins generated by chromosomal translocations play major roles in cancer. Among them, fusions between EWSR1 and transcription factors generate oncogenes with powerful chromatin regulatory activities, capable of establishing complex gene expression programs in permissive precursor cells. Here we define the epigenetic and 3D connectivity landscape of Clear Cell Sarcoma, an aggressive cancer driven by the EWSR1-ATF1 fusion gene. We find that EWSR1-ATF1 displays a distinct DNA binding pattern that requires the EWSR1 domain and promotes ATF1 retargeting to new distal sites, leading to chromatin activation and the establishment of a 3D network that controls oncogenic and differentiation signatures observed in primary CCS tumors. Conversely, EWSR1-ATF1 depletion results in a marked reconfiguration of 3D connectivity, including the emergence of regulatory circuits that promote neural crest-related developmental programs. Taken together, our study elucidates the epigenetic mechanisms utilized by EWSR1-ATF1 to establish regulatory networks in CCS, and points to precursor cells in the neural crest lineage as candidate cells of origin for these tumors.
Identifiants
pubmed: 35477713
doi: 10.1038/s41467-022-29910-4
pii: 10.1038/s41467-022-29910-4
pmc: PMC9046276
doi:
Substances chimiques
Chromatin
0
EWSR1 protein, human
0
EWSR1-ATF1 fusion protein, human
0
Oncogene Proteins, Fusion
0
RNA-Binding Protein EWS
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2267Informations de copyright
© 2022. The Author(s).
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