A predominant enhancer co-amplified with the SOX2 oncogene is necessary and sufficient for its expression in squamous cancer
Yanli Liu,
Zhong Wu,
Jin Zhou,
Dinesh K. A. Ramadurai,
Katelyn L. Mortenson,
Estrella Aguilera-Jimenez,
Yifei Yan,
Xiaojun Yang,
Alison M. Taylor,
Katherine E. Varley,
Jason Gertz,
Peter S. Choi,
Andrew D. Cherniack,
Xingdong Chen,
Adam J. Bass,
Swneke D. Bailey () and
Xiaoyang Zhang ()
Additional contact information
Yanli Liu: Fudan University
Zhong Wu: Sichuan University
Jin Zhou: Sichuan University
Dinesh K. A. Ramadurai: University of Utah
Katelyn L. Mortenson: University of Utah
Estrella Aguilera-Jimenez: University of Utah
Yifei Yan: Research Institute of the McGill University Health Centre
Xiaojun Yang: Northwest Agriculture and Forestry University
Alison M. Taylor: Columbia University
Katherine E. Varley: University of Utah
Jason Gertz: University of Utah
Peter S. Choi: University of Pennsylvania
Andrew D. Cherniack: Harvard Medical School
Xingdong Chen: Fudan University
Adam J. Bass: Harvard Medical School
Swneke D. Bailey: Research Institute of the McGill University Health Centre
Xiaoyang Zhang: Fudan University
Nature Communications, 2021, vol. 12, issue 1, 1-14
Abstract:
Abstract Amplification and overexpression of the SOX2 oncogene represent a hallmark of squamous cancers originating from diverse tissue types. Here, we find that squamous cancers selectively amplify a 3’ noncoding region together with SOX2, which harbors squamous cancer-specific chromatin accessible regions. We identify a single enhancer e1 that predominantly drives SOX2 expression. Repression of e1 in SOX2-high cells causes collapse of the surrounding enhancers, remarkable reduction in SOX2 expression, and a global transcriptional change reminiscent of SOX2 knockout. The e1 enhancer is driven by a combination of transcription factors including SOX2 itself and the AP-1 complex, which facilitates recruitment of the co-activator BRD4. CRISPR-mediated activation of e1 in SOX2-low cells is sufficient to rebuild the e1-SOX2 loop and activate SOX2 expression. Our study shows that squamous cancers selectively amplify a predominant enhancer to drive SOX2 overexpression, uncovering functional links among enhancer activation, chromatin looping, and lineage-specific copy number amplifications of oncogenes.
Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27055-4
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DOI: 10.1038/s41467-021-27055-4
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