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Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells

ABSTRACT: Intra-tumor genetic heterogeneity comes from whole chromosome and/or focal copy number variations (CNVs). We investigated the impact of whole chromosome CNVs on gene expression by performing single-cell RNA sequencing on a chromosomally unstable glioblastoma cancer stem cell (CSC) line and a control normal, diploid neural stem cell (NSC) line. From the gene expression data, we computationally inferred large-scale CNVs in single cells. We find that gene expression across large genomic regions scales proportionally to whole chromosome copy number in chromosomally unstable CSCs. Also, we find that the differential expression of most genes between normal NSCs and glioblastoma CSCs is largely accounted for by copy number alterations. However, we identify 269 genes whose differential expression in glioblastoma CSCs relative to normal NSCs is independent of copy number. Moreover, a gene signature derived from the subset of genes that are differential expressed independent of copy number in glioblastoma CSCs correlates with tumor grade and is prognostic for patient survival. In conclusion, this study demonstrates the utility of single-cell RNA sequencing when analyzing chromosomally unstable cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132172 | GEO | 2019/06/05

REPOSITORIES: GEO

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Project description:Copy number variants (CNVs) reshape gene structure, modulate gene expression, and contribute to significant phenotypic variation. Previous studies have revealed CNV patterns in natural populations of Drosophila melanogaster and suggested that selection and mutational bias shape genomic patterns of CNV. While previous CNV studies focused on heterogeneous strains, here we established a number of second-chromosome substitution lines to uncover CNV characteristics when homozygous. The percentage of genes harboring CNVs is higher than found in previous studies. More CNVs are detected in homozygous than heterozygous substitution strains, suggesting the comparative genomic hybridization arrays underestimate CNV owing to heterozygous masking. We incorporated previous gene expression data collected from some of the same substitution lines to investigate relationships between CNV gene dosage and expression. Most genes present in CNVs show no evidence of increased or diminished transcription, and the fraction of such dosage-insensitive CNVs is greater in heterozygotes. More than 70% of the dosage-sensitive CNVs are recessive with undetectable effects on transcription in heterozygotes. A deficiency of singletons in recessive dosage-sensitive CNVs supports the hypothesis that most CNVs are subject to negative selection. On the other hand, relaxed purifying selection might account for the higher number of protein-protein interactions in dosage insensitive CNVs than in dosage-sensitive CNVs. Dosage-sensitive CNVs that are up-regulated and down-regulated coincide with copy number increases and decreases. Our results help clarify the relation between CNV dosage and gene expression in the D. melanogaster genome. To determine copy number variation, the genomic DNA from five homozygous and two heterozygous second chromosome substitution lines were extracted and compared to another second chromosome substitution line. Gene expression levels can be referred to at Series GSE12191 (Lemos et al. (2008) PMID:18791071).

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Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells

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