A Predominant Enhancer Co-amplified with the SOX2 Oncogene is Necessary and Sufficient for Its Expression in Squamous Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Dec 9

PMID 34880227

Citations 17

Authors

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

Xiaoyang Zhang

Affiliations

Soon will be listed here.

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.

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