Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues

Dan Zhou, Bonnie M. Alver, Shuang Li, Ryan A. Hlady, Joyce J. Thompson, Mark A. Schroeder, Jeong Heon Lee, Jingxin Qiu, Philip H. Schwartz, Jann N Sarkaria, Keith D Robertson

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. Results: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome. Conclusions: Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.

Original languageEnglish (US)
Article number43
JournalGenome Biology
Volume19
Issue number1
DOIs
StatePublished - Mar 27 2018

Fingerprint

Glioma
Cues
stem cells
Stem Cells
stem
Neural Stem Cells
Epigenomics
epigenetics
translocation
Glioblastoma
Transcriptome
DNA
transcriptome
brain
Brain
chemotherapy
stems
Heterografts
gene
Genes

Keywords

  • 5caC
  • 5fC
  • 5hmC
  • 5mC
  • Differentiation
  • Enhancer
  • Epigenome
  • Glioma stem cell
  • Neural stem cell

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Cell Biology

Cite this

Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues. / Zhou, Dan; Alver, Bonnie M.; Li, Shuang; Hlady, Ryan A.; Thompson, Joyce J.; Schroeder, Mark A.; Lee, Jeong Heon; Qiu, Jingxin; Schwartz, Philip H.; Sarkaria, Jann N; Robertson, Keith D.

In: Genome Biology, Vol. 19, No. 1, 43, 27.03.2018.

Research output: Contribution to journalArticle

Zhou, Dan ; Alver, Bonnie M. ; Li, Shuang ; Hlady, Ryan A. ; Thompson, Joyce J. ; Schroeder, Mark A. ; Lee, Jeong Heon ; Qiu, Jingxin ; Schwartz, Philip H. ; Sarkaria, Jann N ; Robertson, Keith D. / Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues. In: Genome Biology. 2018 ; Vol. 19, No. 1.
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abstract = "Background: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. Results: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome. Conclusions: Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.",
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AU - Zhou, Dan

AU - Alver, Bonnie M.

AU - Li, Shuang

AU - Hlady, Ryan A.

AU - Thompson, Joyce J.

AU - Schroeder, Mark A.

AU - Lee, Jeong Heon

AU - Qiu, Jingxin

AU - Schwartz, Philip H.

AU - Sarkaria, Jann N

AU - Robertson, Keith D

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AB - Background: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. Results: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome. Conclusions: Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.

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