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
1Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore. firstname.lastname@example.org email@example.com firstname.lastname@example.org.
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.
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