Research Project
10204029
PROJECT SUMMARY/ABSTRACT. PROJECT 2, D. DARLAND. Functional integration between neural stem cells (NSC) and vascular cells is critical for neural-glia formation during cortical development and glioma progression. Vascular cells can act as epigenetic drivers to induce NSC specification and tumor transformation. However, these epigenetic factors remain poorly defined. We will identify epigenetic mechanisms that regulate NSC fate decisions in response to vascular investment. We have established a unique NSC-vascular coculture system in which NSC adopt a glial fate in response to vascular cues have used a transcriptome-level, unbiased screening approach that has identified Class IIa Hdacs as potential candidates for the epigenetic drivers. Of the histone deacetylases (Hdacs) expressed, only the Class IIa Hdacs expressed in the brain (Hdac 4, Hdac 5, Hdac 7) were upregulated in NSC in vascular coculture, suggesting that they play a role in mediating NSC transition to glial cells. Based on results from the Cancer Genome Atlas (TCGA), elevated levels of Class IIa Hdacs are also associated with human glioma tumor grades, particularly Hdac 4 and Hdac 5. The Class IIa Hdacs have the unique ability to move from the cytoplasm to the nucleus, recruiting protein partners such as Hdac3 and Mecp2 to facilitate deacetylation reactions. This property makes them attractive candidates to transduce microenvironmental cues. We have developed a coculture system that models NSC interactions with vascular cells (endothelial cells and pericytes) and will use this to address the question of NSC fate decisions in response to vascular environmental cues in early cortical development and in a glioma-vascular model. Here we test the hypothesis that changes in Class IIa Hdacs are critical for gliogenesis in response to vascular cell developmental cues and in glioblastoma during cancer progression. In Aim 1 we will test if Class IIa Hdacs are required for gliogenesis in a neural-vascular coculture model. The working hypothesis is that increasing expression of Class IIa Hdacs expression precedes the cell fate transition from NSC to glia under the influence of vascular cell-derived Lif derived. In Aim 2 we will test if Class IIa Hdacs are required for glioma progression in a vascular coculture model. Since Class IIa Hdac are upregulated in human glioblastoma, the working hypothesis is that Class IIa Hdacs are required for the glioblastoma stage transition that occurs in a highly vascular microenvironment. We predict that the Class IIa Hdacs regulate changes in chromatin structure by decreasing transcription of proliferation and stem-specific genes and inducing gliogenesis during development or promoting glioma progression in response to vascular investment. The proposed studies address a critical need to understand how microenvironment-induced, acetylation-based modifications to chromatin influence cortical gliogenesis during development and in glioma tumor progression. The model systems established will also provide a valuable resource for testing potential Class IIa Hdac-based targets for preventing tumor transition in a glioblastoma-vascular cell culture model.
