Defining transcriptional networks and chromatin conformations regulating glioma tumorigenesis

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Malignant gliomas are the most common and deadly primary brain tumor. Despite current therapeutic approaches, most glioma patients die within one year of diagnosis. Genomic instability coupled with aberrant regulation of cell-fate decisions in progenitor cell populations has been linked to glioma, leading to the view that a convergence of genetic mutation and developmental context lead to tumorigenesis. Recent findings demonstrate that a large set of developmental transcription factors are activated in gliomas. These studies suggest that the gene regulatory programs governing glial cell formation are reutilized during glioma formation, pointing to common transcriptional requirements for glial development and tumorigenesis. Therefore, it is critical that we leverage our understanding of glial cell development to gain valuable insights into the biology and treatment of gliomas. We have previously identified a gliogenic transcriptional complex – Sox9/Brn2– that is important for the initiation of gliogenesis. We showed that in a mouse model of malignant glioma disruption of the ability of the complex to bind DNA regulatory elements leads to decreased expression of the glial initiating factor Nuclear Factor-IA (NFIA) and reduced tumorigenesis. Our preliminary data demonstrate that a protein Med12 (Mediator Complex subunit 12), which is expressed during glial cell development, linked to chromatin conformations, and implicated in cancer tumorigenesis, associates with the Sox9/Brn2 complex. Further, reduction of Med12 expression in cortical astrocyte cultures compromises DNA chromatin conformation at the Nfia locus. Therefore, we propose to explore the parallels between embryonic glial development and tumorigenesis by delineating the transcriptional circuitry and regulatory landscape governing glioma tumorigenesis. Analysis of these mechanisms is expected to identify molecular targets important in gliomagenesis. We focus this proposal on the function of a transcriptional complex, important for glial cell differentiation, -Sox9/Brn2/Med12- and its role in coordinating transcriptional mechanisms through gene regulatory elements, and chromatin conformations during gliomagenesis. We will investigate the role of Med12 in glioma formation and tumor cell biology using a wide range of in vitro and in vivo techniques in a novel mouse model of malignant glioma. We will interrogate the mechanisms by which Med12 functions in mediating enhancer/promoter interaction during glioma formation and progression by exploiting recent technological advances that allow for examination of long-range chromatin interactions (i.e. 3C Assays). We will functionally validate downstream target genes of the Sox9/Brn2/Med12 complex that may influence glioma formation. Together, these studies will define how developmentally relevant transcriptional mechanisms including gene regulatory elements and chromatin architecture interface to influence glioma biology and reveal novel gene targets potentially regulating gliomagenesis.