STAG2 loss reshapes oncogenic enhancer-promoter looping in Ewing sarcoma
Name
216802_0_merged_1549393080.pdf
Description
Accepted version
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3.07 MB
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Checksum (MD5)
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Author(s)
Adane, Biniam
Alexe, Gabriela
Seong, Bo Kyung A.
Lu, Diana
Hwang, Elizabeth E.
Hnisz, Denes
Lareau, Caleb A.
Ross, Linda
Lin, Shan
Dela Cruz, Filemon S.
Alternative Title
STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma
Date Issued
June 2021
Journal
Cancer Cell
Publisher
Elsevier BV
Citation
Adane, Biniam et al. "STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma." 39, 6 (June 2016): P827-844.e10. © 2021 Elsevier Inc
Version
Author's final manuscript
Abstract
The core cohesin subunit STAG2 is recurrently mutated in Ewing sarcoma but its biological role is less clear. Here, we demonstrate that cohesin complexes containing STAG2 occupy enhancer and polycomb repressive complex (PRC2)-marked regulatory regions. Genetic suppression of STAG2 leads to a compensatory increase in cohesin-STAG1 complexes, but not in enhancer-rich regions, and results in reprogramming of cis-chromatin interactions. Strikingly, in STAG2 knockout cells the oncogenic genetic program driven by the fusion transcription factor EWS/FLI1 was highly perturbed, in part due to altered enhancer-promoter contacts. Moreover, loss of STAG2 also disrupted PRC2-mediated regulation of gene expression. Combined, these transcriptional changes converged to modulate EWS/FLI1, migratory, and neurodevelopmental programs. Finally, consistent with clinical observations, functional studies revealed that loss of STAG2 enhances the metastatic potential of Ewing sarcoma xenografts. Our findings demonstrate that STAG2 mutations can alter chromatin architecture and transcriptional programs to promote an aggressive cancer phenotype.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/j.ccell.2021.05.007
