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Title: Topography of transcriptionally active chromatin in glioblastoma
Authors: Xu, Liang
Chen, Ye
Huang, Yulun
Sandanaraj, Edwin
Yu, John S.
Lin, Ruby Yu-Tong
Dakle, Pushkar
Ke, Xin-Yu
Chong, Yuk Kien
Koh, Lynnette
Mayakonda, Anand
Nacro, Kassoum
Hill, Jeffrey
Huang, Mo-Li
Gery, Sigal
Lim, See Wee
Huang, Zhengyun
Xu, Ying
Chen, Jianxiang
Bai, Longchuan
Wang, Shaomeng
Wakimoto, Hiroaki
Yeo, Tseng Tsai
Ang, Beng Ti
Müschen, Markus
Tang, Carol
Tan, Tuan Zea
Koeffler, H. Phillip
Keywords: Science::Medicine
Issue Date: 2021
Source: Xu, L., Chen, Y., Huang, Y., Sandanaraj, E., Yu, J. S., Lin, R. Y., Dakle, P., Ke, X., Chong, Y. K., Koh, L., Mayakonda, A., Nacro, K., Hill, J., Huang, M., Gery, S., Lim, S. W., Huang, Z., Xu, Y., Chen, J., ...Koeffler, H. P. (2021). Topography of transcriptionally active chromatin in glioblastoma. Science Advances, 7(18), eabd4676-.
Project: JCO Project 11 03 FG 07 05
Journal: Science Advances 
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.
ISSN: 2375-2548
DOI: 10.1126/sciadv.abd4676
Rights: © 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).
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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