Identifying Core Regulatory Circuitry in Diffuse Intrinsic Pontine Glioma
Mentor: Dr. Suzanne Baker
Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of incurable brain tumors with unique genetic alterations such as the H3K27M mutation co-discovered by our group and others. This mutation is found in approximately 80% of pediatric diffuse gliomas arising in midline structures of the brain, including diffuse intrinsic pontine gliomas (DIPGs), but rarely occurs in HGGs from other brain locations. The striking association between a specific mutation and particular anatomic locations reveals important connections between the process of development and diffuse midline gliomas in children. In normal development, stem cells and progenitor cells give rise to a host of more specialized cell types to direct proper formation and function of the diverse organ systems that build an entire complex organism. Core transcriptional regulatory circuitry (CRC) refers to a limited set of core proteins that regulate which genes are expressed or turned on. CRC factors are typically controlled by regions termed superenhancers, collectively regulate their own expression, and direct lineage-specific expression patterns to create and maintain specialized cell types. In a number of cancers, the CRC reflects the developmental origins of the tumors, can be subverted to contribute to tumor formation, and may be required for tumor cell survival. The clear association between H3K27M mutations and DIPG in children strongly suggest that specific developmental origins are essential for the development of this disease. We hypothesize that the CRC of DIPG will act as central regulators that are required for tumor cell survival. We will use established approaches to identify candidate CRC factors by integrated analyses of superenhancers and patterns of expression in DIPG using our own data and published publicly available data from others. For this proposed POST summer project, we will test a series of candidate CRC factors to identify those that coordinately regulate their own expression and contribute to tumor cell state and survival. These studies will further our understanding of critical processes underlying the development and maintenance of DIPG in children and provide new insights into vulnerabilities of these deadly tumors.
