Liang Xu ^1 2, Ye Chen ¹, Yulun Huang ^3 4 5, Edwin Sandanaraj ^6 7, John S Yu ⁸, Ruby Yu-Tong Lin ⁹, Pushkar Dakle ⁹, Xin-Yu Ke ⁹, Yuk Kien Chong ⁶, Lynnette Koh ^6 10, Anand Mayakonda ⁹, Kassoum Nacro ¹¹, Jeffrey Hill ¹², Mo-Li Huang ^9 13, Sigal Gery ¹⁴, See Wee Lim ⁶, Zhengyun Huang ¹⁵, Ying Xu ¹⁵, Jianxiang Chen ^16 17 18, Longchuan Bai ^19 20, Shaomeng Wang ^{19 20 21 22}, Hiroaki Wakimoto ²³, Tseng Tsai Yeo ²⁴, Beng Ti Ang ^25 26, Markus Müschen ^27 28, Carol Tang ^6 10 29, Tuan Zea Tan ¹, H Phillip Koeffler ^9 14 24

Affiliations

¹Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore. xuliang.zju@gmail.com csicye@nus.edu.sg csittz@nus.edu.sg.
²College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
³Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, China.
⁴Department of Neurosurgery, Medical Center of Soochow University, Suzhou, 215124, China.
⁵Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
⁶Department of Research, National Neuroscience Institute, 308433, Singapore.
⁷Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research, 117609, Singapore.
⁸Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁹Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
¹⁰School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
¹¹Experimental Drug Development Centre, Agency for Science, Technology and Research, 138670, Singapore.
¹²Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
¹³School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
¹⁴Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁵Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, 215123, China.
¹⁶College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China.
¹⁷Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, 311121, China.
¹⁸Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China.
¹⁹Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
²⁰Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
²¹Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
²²Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
²³Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
²⁴National University Cancer Institute, National University Hospital, 119074, Singapore.
²⁵Department of Neurosurgery, National Neuroscience Institute, 308433, Singapore.
²⁶Duke-National University of Singapore Medical School, 169857, Singapore.
²⁷Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
²⁸Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
²⁹Cancer and Stem Cell Biology Program, Duke-National University of Singapore Medical School, 169857, Singapore.

Abstract

Molecular profiling of the most aggressive brain tumor glioblastoma (GBM) on the basis of gene expression, DNA methylation, and genomic variations advances both cancer research and clinical diagnosis. The enhancer architectures and regulatory circuitries governing tumor-intrinsic transcriptional diversity and subtype identity are still elusive. Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across 95 GBM biopsies, 12 normal brain tissues, and 38 cell line counterparts. Analyses of differentially regulated enhancers and super-enhancers uncovered previously unrecognized layers of intertumor heterogeneity. Integrative analysis of variant enhancer loci and transcriptome identified topographies of transcriptional enhancers and core regulatory circuitries in four molecular subtypes of primary tumors: AC1-mesenchymal, AC1-classical, AC2-proneural, and AC3-proneural. Moreover, this study reveals core oncogenic dependency on super-enhancer-driven transcriptional factors, long noncoding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, we provide clinically relevant insights into molecular classification, pathogenesis, and therapeutic intervention of GBM.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

 

PMID: 33931443 DOI: doi.org/10.1126/sciadv.abd4676