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Single Copy Loss of Tet1 disrupts neural stem cell differentiation and enhances GBM aggressiveness

ABSTRACT: Glioblastoma (GBM) is a highly aggressive brain tumor, characterized by poorly differentiated cells that drive disease growth and relapse. In contrast to normal neural stem cells (NSCs) which show a highly orderly process of differentiation, GBM precursors exhibit differentiation failure. In order to identify new mechanisms involved in neuronal differentiation that may have bearing on understanding GBM, we performed an unbiased phenotypic screen, utilizing a library of mouse embryonic stem cell (mESC) clones carrying 1307 unique variable length haplodeletions (altogether covering 25% of the mouse genome). We identified a series of haplodeletions that conferred failed neuronal differentiation following neural lineage specification. Several hit clones contained a deletion on mouse chromosome 10, synteneic to human chromosome 10q, and included the Tet1 gene. Loss of a single allele of Tet1 was sufficient to confer the failed neuronal differentiation on mouse neural precursors by allowing stem cell programs to override early commitment steps leading to full reversion back to a stem cell state. By deleting TET1 in human GBM precursors, we show that loss of one allele of TET1 is sufficient to cause increased self renewal, decreased differentiation, and increased tumorigenicity, demonstrating TET1 to be a key target, along with PTEN, on 10q. Reduced TET1 dosage leads to global DNA hypermethylation and increased sensitivity to DNA methylation inhibitors, suggesting their application in a subset of GBMs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE102136 | GEO | 2023/05/01

REPOSITORIES: GEO

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Project description:All established protocols for differentiation of mouse and human pluripotent stem cells into specific neural subpopulations generate a considerable cellular heterogeneity that hampers experimental and clinical progress. In order to obtain a homogenous population of neuronal precursor cells and to streamline the differentiation of embryonic stem cells (ESCs), we assessed PSA-NCAM, a surface glycoprotein that is specifically expressed on immature neurons. We developed an optimized strategy for magnetic isolation of PSA-NCAM positive neuronal precursors from differentiated ESC cultures and characterized their neuronal differentiation potential in vitro. PSA-NCAM enrichment at an early step of neural differentiation increased the number of ES cell derived neurons and reduced cellular diversity. Gene expression analysis revealed that mainly genes involved in neuronal activity were over-represented after purification. The in vivo potential of in vitro derived PSA-NCAM+ enriched precursors was functionally characterized by grafting into the forebrain of adult mice. Analysis for several neuronal and glia markers at 10 or 40 days post graft showed a distinct differentiation pattern. While unsorted control cells gave rise to a mixed population composed of immature precursors, early postmitotic neurons or glial cells, the majority of PSA-NCAM+ enriched cells differentiated into NeuN positive neurons. Furthermore, when in contact with the rostral migratory stream, higher numbers of cells integrated into the stream and migrated towards the olfactory bulb when the PSA-NCAM enriched population was grafted. Thus, enrichment of neuronal precursors based on PSA-NCAM expression represents a general and straightforward approach to narrow cellular heterogeneity during neuronal differentiation of pluripotent cells. Two conditions (step 4, step 5), each represented by three biological replicates of control and enriched cells (Cy5); mESC was used as common reference (Cy3)

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Single Copy Loss of Tet1 disrupts neural stem cell differentiation and enhances GBM aggressiveness

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