Journal
STEM CELL REPORTS
Volume 5, Issue 5, Pages 829-842Publisher
CELL PRESS
DOI: 10.1016/j.stemcr.2015.09.014
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Funding
- Brain Tumour Charity [8/105]
- Cancer Research UK [A9160]
- Swedish Research Council
- Wenner-Gren foundation
- EMBL
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Wellcome Trust [WT093855]
- Royal Society Wolfson Research Merit Award [WM100023]
- EU-FP7 [257082, 282510]
- Wellcome Beit Memorial research fellowship
- Alex Bolt Research fellowship
- Cancer Research UK Senior Research Fellowship [C25858/A19778]
- Biotechnology and Biological Sciences Research Council [1112564] Funding Source: researchfish
- Cancer Research UK [19680, 17368] Funding Source: researchfish
- Medical Research Council [1297534] Funding Source: researchfish
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Glioblastoma (GBM) is an aggressive brain tumor whose growth is driven by stem cell-like cells. BMP signaling triggers cell-cycle exit and differentiation of GBM stem cells (GSCs) and, therefore, might have therapeutic value. However, the epigenetic mechanisms that accompany differentiation remain poorly defined. It is also unclear whether cell-cycle arrest is terminal. Here we find only a subset of GSC cultures exhibit astrocyte differentiation in response to BMP. Although overtly differentiated non-cycling astrocytes are generated, they remain vulnerable to cell-cycle re-entry and fail to appropriately reconfigure DNA methylation patterns. Chromatin accessibility mapping identified loci that failed to alter in response to BMP and these were enriched in SOX transcription factor-binding motifs. SOX transcription factors, therefore, may limit differentiation commitment. A similar propensity for cell-cycle re-entry and de-differentiation was observed in GSC-derived oligodendrocyte-like cells. These findings highlight significant obstacles to BMP-induced differentiation as therapy for GBM.
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