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Chromatin landscapes reveal developmentally encoded transcriptional states that define human glioblastoma.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2019 May 06; Vol. 216 (5), pp. 1071-1090. Date of Electronic Publication: 2019 Apr 04. - Publication Year :
- 2019
-
Abstract
- Glioblastoma is an incurable brain cancer characterized by high genetic and pathological heterogeneity. Here, we mapped active chromatin landscapes with gene expression, whole exomes, copy number profiles, and DNA methylomes across 44 patient-derived glioblastoma stem cells (GSCs), 50 primary tumors, and 10 neural stem cells (NSCs) to identify essential super-enhancer (SE)-associated genes and the core transcription factors that establish SEs and maintain GSC identity. GSCs segregate into two groups dominated by distinct enhancer profiles and unique developmental core transcription factor regulatory programs. Group-specific transcription factors enforce GSC identity; they exhibit higher activity in glioblastomas versus NSCs, are associated with poor clinical outcomes, and are required for glioblastoma growth in vivo. Although transcription factors are commonly considered undruggable, group-specific enhancer regulation of the MAPK/ERK pathway predicts sensitivity to MEK inhibition. These data demonstrate that transcriptional identity can be leveraged to identify novel dependencies and therapeutic approaches.<br /> (© 2019 Mack et al.)
- Subjects :
- Animals
Brain Neoplasms pathology
Brain Neoplasms surgery
Carcinogenesis genetics
Cell Line, Tumor
Cohort Studies
Gene Expression Regulation, Neoplastic
Glioblastoma pathology
Glioblastoma surgery
Heterografts
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Neoplastic Stem Cells metabolism
Neural Stem Cells metabolism
Transcription Factors genetics
Transcriptome
Brain Neoplasms genetics
Chromatin genetics
Glioblastoma genetics
Transcription, Genetic genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 216
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30948495
- Full Text :
- https://doi.org/10.1084/jem.20190196