High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma.
B7 Antigens
/ antagonists & inhibitors
Brain Neoplasms
/ genetics
Cell Proliferation
Chromatin
/ chemistry
Chromosome Mapping
/ methods
Enhancer Elements, Genetic
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic Heterogeneity
Genome, Human
Genomics
/ methods
Glioblastoma
/ genetics
Humans
Molecular Targeted Therapy
Neoplasm Proteins
/ classification
Neoplastic Stem Cells
/ metabolism
Primary Cell Culture
RNA, Small Interfering
/ genetics
Transcription, Genetic
Journal
Genome research
ISSN: 1549-5469
Titre abrégé: Genome Res
Pays: United States
ID NLM: 9518021
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
16
11
2018
accepted:
26
06
2019
pubmed:
30
6
2019
medline:
1
2
2020
entrez:
29
6
2019
Statut:
ppublish
Résumé
We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including
Identifiants
pubmed: 31249064
pii: gr.246520.118
doi: 10.1101/gr.246520.118
pmc: PMC6673710
doi:
Substances chimiques
B7 Antigens
0
CD276 protein, human
0
Chromatin
0
Neoplasm Proteins
0
RNA, Small Interfering
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1211-1222Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
© 2019 Johnston et al.; Published by Cold Spring Harbor Laboratory Press.
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