Dataset Information

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

ABSTRACT: Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling. Our study characterizes oncogenic and developmental programs in H3K27M-glioma at single-cell resolution and across genetic subclones, suggesting potential therapeutic targets in this disease.

SUBMITTER: Filbin MG

PROVIDER: S-EPMC5949869 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

Filbin Mariella G MG Tirosh Itay I Hovestadt Volker V Shaw McKenzie L ML Escalante Leah E LE Mathewson Nathan D ND Neftel Cyril C Frank Nelli N Pelton Kristine K Hebert Christine M CM Haberler Christine C Yizhak Keren K Gojo Johannes J Egervari Kristof K Mount Christopher C van Galen Peter P Bonal Dennis M DM Nguyen Quang-De QD Beck Alexander A Sinai Claire C Czech Thomas T Dorfer Christian C Goumnerova Liliana L Lavarino Cinzia C Carcaboso Angel M AM Mora Jaume J Mylvaganam Ravindra R Luo Christina C CC Peyrl Andreas A Popović Mara M Azizi Amedeo A Batchelor Tracy T TT Frosch Matthew P MP Martinez-Lage Maria M Kieran Mark W MW Bandopadhayay Pratiti P Beroukhim Rameen R Fritsch Gerhard G Getz Gad G Rozenblatt-Rosen Orit O Wucherpfennig Kai W KW Louis David N DN Monje Michelle M Slavc Irene I Ligon Keith L KL Golub Todd R TR Regev Aviv A Bernstein Bradley E BE Suvà Mario L ML

Science (New York, N.Y.) 20180401 6386

Gliomas with histone H3 lysine27-to-methionine mutations (H3K27M-glioma) arise primarily in the midline of the central nervous system of young children, suggesting a cooperation between genetics and cellular context in tumorigenesis. Although the genetics of H3K27M-glioma are well characterized, their cellular architecture remains uncharted. We performed single-cell RNA sequencing in 3321 cells from six primary H3K27M-glioma and matched models. We found that H3K27M-glioma primarily contain cells ...[more]

PMID: 29674595

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Project description:We report transcriptomes from 430 single glioblastoma cells isolated from 5 individual tumors and 102 single cells from gliomasphere cells lines generated using SMART-seq. In addition, we report population RNA-seq from the five tumors as well as RNA-seq from cell lines derived from 3 tumors (MGH26, MGH28, MGH31) cultured under serum free (CSC) and differentiated (FCS) conditions. This dataset highlights intratumoral heterogeneity with regards to the expression of de novo derived transcriptional modules and established subtype classifiers. Operative specimens from five glioblastoma patients (MGH26, MGH28, MGH29, MGH30, MGH31) were acutely dissociated, depleted for CD45+ inflammatory cells and then sorted as single cells (576 samples). Population controls for each tumor were isolated by sorting 2000-10000 cells and processed in parallel (5 population control samples). Single cells from two established cell lines, GBM6 and GBM8, were also sorted as single cells (192 samples). SMART-seq protocol was implemented to generate single cell full length transcriptomes (modified from Shalek, et al Nature 2013) and sequenced using 25 bp paired end reads. Single cell cDNA libraries for MGH30 were resequenced using 100 bp paired end reads to allow for isoform and splice junction reconstruction (96 samples, annotated MGH30L). Cells were also cultured in serum free conditions to generate gliomasphere cell lines for MGH26, MGH28, and MGH31 (CSC) which were then differentiated using 10% serum (FCS). Population RNA-seq was performed on these samples (3 CSC, 3 FCS, 6 total). The initial dataset included 875 RNA-seq libraries (576 single glioblastoma cells, 96 resequenced MGH30L, 192 single gliomasphere cells, 5 tumor population controls, 6 population libraries from CSC and FCS samples). Data was processed as described below using RSEM for quantification of gene expression. 5,948 genes with the highest composite expression either across all single cells combined (average log2(TPM)>4.5) or within a single tumor (average log2(TPM)>6 in at least one tumor) were included. Cells expressing less than 2,000 of these 5,948 genes were excluded. The final processed dataset then included 430 primary single cell glioblastoma transcriptomes, 102 single cell transcriptomes from cell lines(GBM6,GBM8), 5 population controls (1 for each tumor), and 6 population libraries from cell lines derived from the tumors (CSC and FCS for MGH26, MGH28 and MGH31). The final matrix (GBM_data_matrix.txt) therefore contains 5948 rows (genes) quantified in 543 samples (columns). Please note that the samples which are not included in the data processing are indicated in the sample description field.

Dataset Information

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

Publications

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq.

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