Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states.
Brain Neoplasms
/ genetics
Cell Line, Tumor
Cell Plasticity
/ genetics
CpG Islands
/ genetics
DNA Copy Number Variations
/ genetics
DNA Methylation
/ genetics
Epigenesis, Genetic
Glioma
/ genetics
Humans
Inheritance Patterns
/ genetics
Isocitrate Dehydrogenase
/ genetics
Phylogeny
Polycomb Repressive Complex 2
/ metabolism
Promoter Regions, Genetic
/ genetics
Single-Cell Analysis
Transcription, Genetic
Transcriptome
/ genetics
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
09
09
2020
accepted:
30
07
2021
pubmed:
2
10
2021
medline:
10
11
2021
entrez:
1
10
2021
Statut:
ppublish
Résumé
Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.
Identifiants
pubmed: 34594037
doi: 10.1038/s41588-021-00927-7
pii: 10.1038/s41588-021-00927-7
pmc: PMC8675181
mid: NIHMS1760761
doi:
Substances chimiques
Isocitrate Dehydrogenase
EC 1.1.1.41
Polycomb Repressive Complex 2
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1469-1479Subventions
Organisme : NCI NIH HHS
ID : K99 CA248955
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : NCI NIH HHS
ID : K12 CA090354
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA258763
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA202820
Pays : United States
Organisme : NCI NIH HHS
ID : DP2 CA239065
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA180922
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA245523
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NHGRI NIH HHS
ID : RM1 HG011014
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
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