Topography of transcriptionally active chromatin in glioblastoma

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 and others, (2021) Topography of transcriptionally active chromatin in glioblastoma. Science Advances, 7 (18). pp. 1-17. ISSN 2375-2548

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 24 Sep 2021 15:03
Last Modified: 30 Nov 2021 16:40
URI: http://sro.sussex.ac.uk/id/eprint/101900

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