Abstract
Glioblastoma, the most common primary malignant brain tumor, harbors a small population of tumor initiating cells (glioblastoma stem cells) that have many properties similar to neural stem cells. To investigate common regulatory networks in both neural and glioblastoma stem cells, we subjected both cell types to in-vitro differentiation conditions and measured global gene-expression changes using gene expression microarrays. Analysis of enriched transcription factor DNA-binding sites in the promoters of differentially expressed genes was used to reconstruct regulatory networks involved in differentiation. Computational predictions, which were biochemically validated, show an extensive overlap of regulatory circuitry between cell types including a network centered on the transcription factor KLF4. We further demonstrate that EGR1, a transcription factor previously shown to be downstream of the MAPK pathway, regulates KLF4 expression and that KLF4 in turn transcriptionally activates NOTCH as well as SOX2. These results demonstrate how known genomic alterations in glioma that induce constitutive activation of MAPK are transcriptionally linked to master regulators essential for neural stem cell identify.
Highlights
Murine models of gliomagenesis have supported the hypothesis that gliomas originate from normal neural stem cells
Common transcription factors include those known to be important in NSC biology such as SOX2, KLF4, EGR1, HES1, and OLIG1/2
Further analysis of 3 neural stem cell lines derived from primary human brain tissue agreed with the findings from NSC E14 in the identification of a core set of transcription factor binding motifs representing SOX, EGR1, HES1, and KLF4 (Fig. 3)[19]
Summary
Murine models of gliomagenesis have supported the hypothesis that gliomas originate from normal neural stem cells. A number of different studies have used global gene expression changes and other genome-wide assays during NSC differentiation to identify master regulators and pathways[13,14]. Given the importance of the proneural clinical subtype of glioblastoma, we asked whether differentiation-induced global gene expression changes in 5 GSC derived from 5 parental proneural tumors could reveal type-specific master regulators. We sought to compare regulatory networks between proneural GSC and neural stem cells with the aim to elucidate how pathways affected by genomic alterations specific to glioma could act to induce constitutive activation of master regulators important for neural stem identity and self-renewal. Identification of a network of neural stem-related regulators in GSCs and how these regulators are connected to oncogenic pathways in glioma could potentially lead to new treatment strategies designed to induce differentiation in GSCs and halt tumor progression
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