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Characterizing the epigenome of glioma stem cells (Methylation BeadChip)

ABSTRACT: Glioma initiating cells/stem cells exist in the bulk tumor of glioblastoma. This cell population contributes to the frequent resistances toward radiation/chemotherapy, aggressiveness of adult brain cancer and increased recurrence rate. Targeting stem cell population becomes one the most promising and permissive therapeutic strategies. We isolated glioma stem cells from patient-derived xenografts and profiled their epigenomic features, including 4 different DNA marks and 2 enhancer marks, and transcriptome in these in vitro cultured cell lines. Three fetal brain-derived neural stem/progenitors cells were used for comparing the unique and common molecular features in these glioma cancer stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE92462 | GEO | 2018/02/23

REPOSITORIES: GEO

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Project description:The recent identification of cancer stem cells (CSCs) in multiple human cancers provides a new inroad to understanding tumorigenesis at the cellular level. CSCs are defined by their characteristics of self-renewal, multipotentiality, and tumor initiation upon transplantation. By testing for these defining characteristics, we provide evidence for the existence of CSCs in a transgenic mouse model of glioma, S100Ã-verbB;Trp53. In this glioma model, CSCs are enriched in the side-population (SP) cells. These SP cells have enhanced tumor-initiating capacity, self-renewal, and multipotentiality compared to non-SP cells from the same tumors. Furthermore, gene expression analysis comparing FACS-sorted cancer SP cells to non-SP cancer cells and normal neural SP cells identified 45 candidate genes that are differentially expressed in glioma stem cells. We validated the expression of two genes from this list (S100a4 and S100a6) in primary mouse gliomas and human glioma samples. Analyses of xenografted human GBM (glioblatoma multiforme) cell lines and primary human glioma tissues show that S100A4 and S100A6 are expressed in a small subset of cancer cells and that their abundance is positively correlated to tumor grade. In conclusion, this study shows that CSCs exist in a mouse glioma model, suggesting that this model can be used to study the molecular and cellular characteristics of CSCs in vivo and to further test the cancer stem cell hypothesis. Experiment Overall Design: This study features two factors, injected cell origin (either tumorsphere or neurosphere) and FACS cell population (either side population or non-side population cells). There were two different tumorspheres, labeled 3447 and 4346 that were isolated from brain tumors in S100beta-verbB;p53-/- or S100beta-verbB;p53+/- mice. The tumorspheres were injected separately into the brains of NOD.Cg-Prkdc<scid>Il2rg<tm1Wjl>/SzJ mice to generate biological triplicates of each primary tumor. Tumorspheres were isolated and cultured before FACS sorting to obtain side population and non-side population cells. As a control, untransformed neurospheres from three independent S100beta-verbB;p53-/- or S100beta-verbB;p53+/- mice were isolated, cultured, and FACS sorted to obtain side population and non-side population cells. Side population and non-side population cells cultured from three mice injected with the 3447 cultured tumorspheres were assayed for gene expression (six samples). Side-population stem cells cultured from three mice injected with the 4346 cultured tumorspheres were assayed for gene expression (three samples). Side-population and non-side population cells cultured from three mice injected with the neurospheres were assayed for gene expression (six samples).

Project description:Aberrational epigenetic marks are believed to play a major role in establishing the abnormal features of cancer cells. Rational use and development of drugs aimed at epigenetic processes requires an understanding of the range, extent, and roles of epigenetic reprogramming in cancer cells. Using ChIP-chip and MeDIP-chip approaches, we localized well-established and prevalent epigenetic marks (H3K27me3, H3K4me3, H3K9me3, DNA methylation) on a genome scale in several lines of putative glioma stem cells (brain tumor stem cells, BTSCs) and, for comparison, normal human fetal neural stem cells (fNSCs). We determined a substantial M-bM-^@M-^\coreM-bM-^@M-^] set of promoters possessing each mark in every surveyed BTSC cell type, which largely overlapped the corresponding fNSC sets. However, there was substantial diversity among cell types in mark localization. We observed large differences among cell types in total number of H3K9me3+ positive promoters and peaks and in broad modification areas for H3K27me3 and, to a lesser extent, H3K9me3. We verified that a change in a broad modification (defined as >50 kb peak length) affected gene expression of CACNG7. We detected large numbers of bivalent promoters, but most bivalent promoters did not display direct overlap of contrasting epigenetic marks, but rather occupied nearby regions of the proximal promoter. There were significant differences in the sets of promoters bearing bivalent marks in the different cell types and few consistent differences between fNSCs and BTSCs. Overall, our M-bM-^@M-^\core setM-bM-^@M-^] data establishes sets of potential therapeutic targets, but the diversity in sets of sites and broad modifications among cell types underscores the need to carefully consider BTSC subtype variation in epigenetic therapy. Our results point toward substantial differences among cell types in the activity of the production/maintenance systems for H3K9me3 and for broad regions of modification (H3K27me3 or H3K9me3). Finally, the unexpected diversity in bivalent promoter sets among these multipotent cells indicates that bivalent promoters may play complex roles in the overall biology of these cells. These results provide key information for forming the basis for future rational drug therapy aimed at epigenetic processes in these cells. ChIP-chip and MeDIP-chip localization of histone modifications and DNA methylation in glioma stem cells and fetal neural stem cells comparison of 4 lines of brain tumor stem cells to each other and to normal fetal neural stem cells

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Characterizing the epigenome of glioma stem cells (Methylation BeadChip)

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