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A CHD8-TRRAP axis facilitates MYC and E2F target gene regulation in human neural stem cells. [ChIP-seq]

ABSTRACT: Mutations in ATP-dependent chromatin remodeler CHD8 cause one of the most frequent monogenetic forms of autism and is associated with brain overgrowth. Nevertheless, the activities of CHD8 in autism-relevant cell types are still poorly understood. Here, we purify the CHD8 protein from human neural stem cells and determine its interaction partners using mass spectrometry. We identify the TRRAP complex, a coactivator of MYC and E2F transcription factors, as a prominent CHD8 interaction partner. CHD8 colocalizes genome-wide with TRRAP and bind together at MYC and E2F target gene promoters in human neural stem cells. Depletion of CHD8 or TRRAP in human neural stem cells shows downregulation of MYC and E2F target genes as the most prominent gene-regulatory events. MYC and E2F transcription factors are established oncogenes known to regulate cell growth. Our results link CHD8 to TRRAP and suggest they act together in facilitating the regulation of MYC and E2F target genes in neural stem cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247132 | GEO | 2024/11/06

REPOSITORIES: GEO

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Project description:Glioblastoma multiforme is the most common and most aggressive type of primary brain tumor. The brain-infiltrative character of glioblastoma makes complete surgical removal of the tumor impossible and neither radiation nor current chemotherapy provide cure. Recent evidence shows that glioblastoma multiforme consists of heterogeneous cell populations which differ in tumor-forming potential. Enriched tumor-initiating capacity has been linked to poorly differentiated glioblastoma cells sharing features with neural stem cells. Thus, these cells are important targets for new therapeutic strategies. We aim to identify novel targets controlling maintenance and differentiation in glioblastoma-initiating cells through high throughput screening. To this end, we utilized libraries of small chemical compounds and small interference RNAs in combination with automated imaging and data analysis. Patient-derived glioblastoma cells were expanded and characterized using neural stem cell conditions. In culture, the cells showed low differentiation but expression of neural stem cell markers such as Nestin and Sox2. Upon intracranial injection into SCID mice these cells gave rise to tumors displaying the hallmarks of the human disease. Differentiation of glioblastoma-initiating cells (for example elicited through bone morphogenetic protein, BMP) was associated with strong morphological changes. Hence, cellular morphology, as well as markers specific for differentiation or death were used as screen readout. Lentiviral RNA interference-based screening yielded several gene knockdowns leading to ‘forced’ differentiation of glioblastoma-initiating cells. For example, knockdown of TRRAP (transformation/transcription domain associated protein) led to strongly increased differentiation and loss of proliferative and self-renewing capacity in these cells. TRRAP is an adapter protein implicated in oncogenic transformation through c-MYC transcription activation, also participating in chromatin remodeling and DNA repair. Glioblastoma-initiating cells with reduced TRRAP displayed increased apoptosis upon treatment with the genotoxic agent temozolomide. In vivo, Trapp knockdown cells were not able to give rise to glioblastoma upon transplantation into the brain of SCID mice. Together, these findings support a crucial role for TRRAP in maintenance and tumorigenicity of glioblastoma-initiating cells and might offer future therapeutic options. Two treatments compared to control: two different shRNA sequences for TRRAP were compared to a control shRNA sequence in their effects on global transcription in brain tumor initiating cells

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A CHD8-TRRAP axis facilitates MYC and E2F target gene regulation in human neural stem cells. [ChIP-seq]

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