2. Academic Validation
  3. Topography of transcriptionally active chromatin in glioblastoma

Topography of transcriptionally active chromatin in glioblastoma

  • Sci Adv. 2021 Apr 30;7(18):eabd4676. doi: 10.1126/sciadv.abd4676.
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

Affiliations

  • 1 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore. xuliang.zju@gmail.com csicye@nus.edu.sg csittz@nus.edu.sg.
  • 2 College of Life Sciences, Zhejiang University, Hangzhou, 310058, China.
  • 3 Department of Neurosurgery, Dushu Lake Hospital Affiliated of Soochow University, Suzhou, 215124, China.
  • 4 Department of Neurosurgery, Medical Center of Soochow University, Suzhou, 215124, China.
  • 5 Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China.
  • 6 Department of Research, National Neuroscience Institute, 308433, Singapore.
  • 7 Singapore Institute for Clinical Sciences, Agency for Science, Technology, and Research, 117609, Singapore.
  • 8 Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 9 Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore.
  • 10 School of Biological Sciences, Nanyang Technological University, 637551, Singapore.
  • 11 Experimental Drug Development Centre, Agency for Science, Technology and Research, 138670, Singapore.
  • 12 Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton BN1 9QJ, UK.
  • 13 School of Biology and Basic Medical Sciences, Soochow University, Suzhou, 215123, China.
  • 14 Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
  • 15 Cambridge-Suda Genomic Research Center, Soochow University, Suzhou, 215123, China.
  • 16 College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou, 311121, China.
  • 17 Key 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.
  • 18 Department of Hepatology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, 310015, China.
  • 19 Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
  • 20 Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
  • 21 Department of Pharmacology, University of Michigan, Ann Arbor, MI 48109, USA.
  • 22 Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
  • 23 Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 24 National University Cancer Institute, National University Hospital, 119074, Singapore.
  • 25 Department of Neurosurgery, National Neuroscience Institute, 308433, Singapore.
  • 26 Duke-National University of Singapore Medical School, 169857, Singapore.
  • 27 Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06511, USA.
  • 28 Department of Immunobiology, Yale University, New Haven, CT 06511, USA.
  • 29 Cancer and Stem Cell Biology Program, Duke-National University of Singapore Medical School, 169857, Singapore.
PMID: 33931443 DOI: 10.1126/sciadv.abd4676
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.

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