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A Core Regulatory Circuit in Glioblastoma Stem Cells Links MAPK Activation to a Transcriptional Program of Neural Stem Cell Identity.

TitleA Core Regulatory Circuit in Glioblastoma Stem Cells Links MAPK Activation to a Transcriptional Program of Neural Stem Cell Identity.
Publication TypeJournal Article
Year of Publication2017
AuthorsRiddick G, Kotliarova S, Rodriguez V, Kim HS, Linkous A, Storaska AJ, Ahn S, Walling J, Belova G, Fine HA
JournalSci Rep
Volume7
Pagination43605
Date Published2017 03 03
ISSN2045-2322
KeywordsAnimals, Binding Sites, Biomarkers, Brain Neoplasms, Cell Line, Tumor, Computational Biology, Disease Progression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genome-Wide Association Study, Glioblastoma, Humans, Mice, Mitogen-Activated Protein Kinases, Neoplasm Grading, Neoplastic Stem Cells, Neural Stem Cells, Protein Binding, Signal Transduction, Transcription Factors, Transcriptome
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.

DOI10.1038/srep43605
Alternate JournalSci Rep
PubMed ID28256619
PubMed Central IDPMC5335262