Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells
Abstract Background Intra-tumor heterogeneity stems from genetic, epigenetic, functional, and environmental differences among tumor cells. A major source of genetic heterogeneity comes from DNA sequence differences and/or whole chromosome and focal copy number variations (CNVs). Whole chromosome CNV...
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| Format: | Article |
| Language: | English |
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BMC
2019-05-01
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| Series: | BMC Medical Genomics |
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| Online Access: | http://link.springer.com/article/10.1186/s12920-019-0532-5 |
| _version_ | 1818407360280920064 |
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| author | Yanding Zhao Robert Carter Sivaraman Natarajan Frederick S. Varn Duane A. Compton Charles Gawad Chao Cheng Kristina M. Godek |
| author_facet | Yanding Zhao Robert Carter Sivaraman Natarajan Frederick S. Varn Duane A. Compton Charles Gawad Chao Cheng Kristina M. Godek |
| author_sort | Yanding Zhao |
| collection | DOAJ |
| description | Abstract Background Intra-tumor heterogeneity stems from genetic, epigenetic, functional, and environmental differences among tumor cells. A major source of genetic heterogeneity comes from DNA sequence differences and/or whole chromosome and focal copy number variations (CNVs). Whole chromosome CNVs are caused by chromosomal instability (CIN) that is defined by a persistently high rate of chromosome mis-segregation. Accordingly, CIN causes constantly changing karyotypes that result in extensive cell-to-cell genetic heterogeneity. How the genetic heterogeneity caused by CIN influences gene expression in individual cells remains unknown. Methods We performed single-cell RNA sequencing on a chromosomally unstable glioblastoma cancer stem cell (CSC) line and a control normal, diploid neural stem cell (NSC) line to investigate the impact of CNV due to CIN on gene expression. From the gene expression data, we computationally inferred large-scale CNVs in single cells. Also, we performed copy number adjusted differential gene expression analysis between NSCs and glioblastoma CSCs to identify copy number dependent and independent differentially expressed genes. Results Here, we demonstrate that gene expression across large genomic regions scales proportionally to whole chromosome copy number in chromosomally unstable CSCs. Also, we show 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. Conclusions These results demonstrate that CIN is directly responsible for gene expression changes and contributes to both genetic and transcriptional heterogeneity among glioblastoma CSCs. These results also demonstrate that the expression of some genes is buffered against changes in copy number, thus preserving some consistency in gene expression levels from cell-to-cell despite the continuous change in karyotype driven by CIN. Importantly, a gene signature derived from the subset of genes whose expression is buffered against copy number alterations correlates with tumor grade and is prognostic for patient survival that could facilitate patient diagnosis and treatment. |
| first_indexed | 2024-12-14T09:26:36Z |
| format | Article |
| id | doaj.art-97ce881b83ec43f092d71709a1835645 |
| institution | Directory Open Access Journal |
| issn | 1755-8794 |
| language | English |
| last_indexed | 2024-12-14T09:26:36Z |
| publishDate | 2019-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medical Genomics |
| spelling | doaj.art-97ce881b83ec43f092d71709a18356452022-12-21T23:08:10ZengBMCBMC Medical Genomics1755-87942019-05-0112111610.1186/s12920-019-0532-5Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cellsYanding Zhao0Robert Carter1Sivaraman Natarajan2Frederick S. Varn3Duane A. Compton4Charles Gawad5Chao Cheng6Kristina M. Godek7Department of Molecular and Systems Biology, Geisel School of Medicine at DartmouthDepartments of Oncology and Computational Biology, St. Jude Children’s Research HospitalDepartments of Oncology and Computational Biology, St. Jude Children’s Research HospitalDepartment of Molecular and Systems Biology, Geisel School of Medicine at DartmouthDepartment of Biochemistry and Cell Biology, HB7200, Geisel School of Medicine at DartmouthDepartments of Oncology and Computational Biology, St. Jude Children’s Research HospitalDepartment of Molecular and Systems Biology, Geisel School of Medicine at DartmouthDepartment of Biochemistry and Cell Biology, HB7200, Geisel School of Medicine at DartmouthAbstract Background Intra-tumor heterogeneity stems from genetic, epigenetic, functional, and environmental differences among tumor cells. A major source of genetic heterogeneity comes from DNA sequence differences and/or whole chromosome and focal copy number variations (CNVs). Whole chromosome CNVs are caused by chromosomal instability (CIN) that is defined by a persistently high rate of chromosome mis-segregation. Accordingly, CIN causes constantly changing karyotypes that result in extensive cell-to-cell genetic heterogeneity. How the genetic heterogeneity caused by CIN influences gene expression in individual cells remains unknown. Methods We performed single-cell RNA sequencing on a chromosomally unstable glioblastoma cancer stem cell (CSC) line and a control normal, diploid neural stem cell (NSC) line to investigate the impact of CNV due to CIN on gene expression. From the gene expression data, we computationally inferred large-scale CNVs in single cells. Also, we performed copy number adjusted differential gene expression analysis between NSCs and glioblastoma CSCs to identify copy number dependent and independent differentially expressed genes. Results Here, we demonstrate that gene expression across large genomic regions scales proportionally to whole chromosome copy number in chromosomally unstable CSCs. Also, we show 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. Conclusions These results demonstrate that CIN is directly responsible for gene expression changes and contributes to both genetic and transcriptional heterogeneity among glioblastoma CSCs. These results also demonstrate that the expression of some genes is buffered against changes in copy number, thus preserving some consistency in gene expression levels from cell-to-cell despite the continuous change in karyotype driven by CIN. Importantly, a gene signature derived from the subset of genes whose expression is buffered against copy number alterations correlates with tumor grade and is prognostic for patient survival that could facilitate patient diagnosis and treatment.http://link.springer.com/article/10.1186/s12920-019-0532-5GlioblastomaCancer stem cellsCSCsChromosomal instabilityCINAneuploidy |
| spellingShingle | Yanding Zhao Robert Carter Sivaraman Natarajan Frederick S. Varn Duane A. Compton Charles Gawad Chao Cheng Kristina M. Godek Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells BMC Medical Genomics Glioblastoma Cancer stem cells CSCs Chromosomal instability CIN Aneuploidy |
| title | Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| title_full | Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| title_fullStr | Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| title_full_unstemmed | Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| title_short | Single-cell RNA sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| title_sort | single cell rna sequencing reveals the impact of chromosomal instability on glioblastoma cancer stem cells |
| topic | Glioblastoma Cancer stem cells CSCs Chromosomal instability CIN Aneuploidy |
| url | http://link.springer.com/article/10.1186/s12920-019-0532-5 |
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