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Topography of transcriptionally active chromatin in glioblastoma

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 div...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087410/
https://www.ncbi.nlm.nih.gov/pubmed/33931443
http://dx.doi.org/10.1126/sciadv.abd4676
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author 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
author_facet 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
author_sort Xu, Liang
collection PubMed
description 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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spelling pubmed-80874102021-05-13 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 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 Sci Adv Research Articles 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. American Association for the Advancement of Science 2021-04-30 /pmc/articles/PMC8087410/ /pubmed/33931443 http://dx.doi.org/10.1126/sciadv.abd4676 Text en 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). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Research Articles
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
Topography of transcriptionally active chromatin in glioblastoma
title Topography of transcriptionally active chromatin in glioblastoma
title_full Topography of transcriptionally active chromatin in glioblastoma
title_fullStr Topography of transcriptionally active chromatin in glioblastoma
title_full_unstemmed Topography of transcriptionally active chromatin in glioblastoma
title_short Topography of transcriptionally active chromatin in glioblastoma
title_sort topography of transcriptionally active chromatin in glioblastoma
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087410/
https://www.ncbi.nlm.nih.gov/pubmed/33931443
http://dx.doi.org/10.1126/sciadv.abd4676
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