Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma

Rajendra P. Pangeni, Zhou Zhang, Angel A Alvarez, Xuechao Wan, Namratha Sastry, Songjian Lu, Taiping Shi, Tianzhi Huang, Charles X. Lei, Charles David James, John Kessler, Cameron W. Brennan, Ichiro Nakano, Xinghua Lu, Bo Hu, Wei Zhang, Shi-Yuan Cheng*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.

Original languageEnglish (US)
Pages (from-to)432-448
Number of pages17
JournalEpigenetics
Volume13
Issue number4
DOIs
StatePublished - Apr 3 2018

Fingerprint

Glioblastoma
Epigenomics
Glioma
Stem Cells
Genome
DNA Methylation
Neoplasms
Atlases
Methylation
Gene Expression
Neoplastic Stem Cells
Gene Expression Profiling
Survival Analysis
Decision Making

Keywords

  • DNA methylation
  • Glioma stem-like cells (GSC)
  • glioblastoma (GBM)
  • prognostic accuracy
  • transcriptome signatures

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Pangeni, Rajendra P. ; Zhang, Zhou ; Alvarez, Angel A ; Wan, Xuechao ; Sastry, Namratha ; Lu, Songjian ; Shi, Taiping ; Huang, Tianzhi ; Lei, Charles X. ; James, Charles David ; Kessler, John ; Brennan, Cameron W. ; Nakano, Ichiro ; Lu, Xinghua ; Hu, Bo ; Zhang, Wei ; Cheng, Shi-Yuan. / Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma. In: Epigenetics. 2018 ; Vol. 13, No. 4. pp. 432-448.
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Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma. / Pangeni, Rajendra P.; Zhang, Zhou; Alvarez, Angel A; Wan, Xuechao; Sastry, Namratha; Lu, Songjian; Shi, Taiping; Huang, Tianzhi; Lei, Charles X.; James, Charles David; Kessler, John; Brennan, Cameron W.; Nakano, Ichiro; Lu, Xinghua; Hu, Bo; Zhang, Wei; Cheng, Shi-Yuan.

In: Epigenetics, Vol. 13, No. 4, 03.04.2018, p. 432-448.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma

AU - Pangeni, Rajendra P.

AU - Zhang, Zhou

AU - Alvarez, Angel A

AU - Wan, Xuechao

AU - Sastry, Namratha

AU - Lu, Songjian

AU - Shi, Taiping

AU - Huang, Tianzhi

AU - Lei, Charles X.

AU - James, Charles David

AU - Kessler, John

AU - Brennan, Cameron W.

AU - Nakano, Ichiro

AU - Lu, Xinghua

AU - Hu, Bo

AU - Zhang, Wei

AU - Cheng, Shi-Yuan

PY - 2018/4/3

Y1 - 2018/4/3

N2 - Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.

AB - Glioma stem cells (GSCs), a subpopulation of tumor cells, contribute to tumor heterogeneity and therapy resistance. Gene expression profiling classified glioblastoma (GBM) and GSCs into four transcriptomically-defined subtypes. Here, we determined the DNA methylation signatures in transcriptomically pre-classified GSC and GBM bulk tumors subtypes. We hypothesized that these DNA methylation signatures correlate with gene expression and are uniquely associated either with only GSCs or only GBM bulk tumors. Additional methylation signatures may be commonly associated with both GSCs and GBM bulk tumors, i.e., common to non-stem-like and stem-like tumor cell populations and correlating with the clinical prognosis of glioma patients. We analyzed Illumina 450K methylation array and expression data from a panel of 23 patient-derived GSCs. We referenced these results with The Cancer Genome Atlas (TCGA) GBM datasets to generate methylomic and transcriptomic signatures for GSCs and GBM bulk tumors of each transcriptomically pre-defined tumor subtype. Survival analyses were carried out for these signature genes using publicly available datasets, including from TCGA. We report that DNA methylation signatures in proneural and mesenchymal tumor subtypes are either unique to GSCs, unique to GBM bulk tumors, or common to both. Further, dysregulated DNA methylation correlates with gene expression and clinical prognoses. Additionally, many previously identified transcriptionally-regulated markers are also dysregulated due to DNA methylation. The subtype-specific DNA methylation signatures described in this study could be useful for refining GBM sub-classification, improving prognostic accuracy, and making therapeutic decisions.

KW - DNA methylation

KW - Glioma stem-like cells (GSC)

KW - glioblastoma (GBM)

KW - prognostic accuracy

KW - transcriptome signatures

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