Epigenetic pathways and cell cycle exit

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PROPOSAL SUMMARY Medulloblastoma is the most common pediatric brain tumor. Although some forms of medulloblastoma are treatable by surgery and chemotherapy, others are resistant to the standard of care. In addition, behavioral and cognitive deficits plague many medulloblastoma patients. Therefore, new therapeutic options are needed for treating medulloblastoma. Inhibitors of the epigenetic reader protein Brd4 are currently being tried in medulloblastoma patients due to their potential ability to reduce drivers of medulloblastoma growth including MYC. However, the underlying biology of Brd4 in the developing brain is not understood. We have recently shown that Brd4 knockout during development leads to cerebellar ataxia. We also demonstrated that Brd4 regulation via phosphorylation occurs during cell cycle exit of cerebellar granule cell progenitors. However, the functional importance of this regulation is unclear. In the proposed studies we will determine whether Brd4 phosphorylation is part of a switch-like mechanism controlling cell proliferation and cell cycle exit in GCPs and whether dysregulation of this process contributes to medulloblastoma. In Aim 1, we will determine the Brd4 signaling pathways important for GCP cell cycle exit. In Aim 2 we will determine the role of two upstream kinases CK1d and CK2a in controlling Brd4 activity and cell cycle exit. In Aim 3, we will determine the consequence of modulating Brd4 levels and phosphorylation status on progression of mouse medulloblastoma. Collectively, these studies will reveal the importance of the epigenetic reader protein Brd4 in the decision to proliferate or exit the cell cycle, which is critical for regulated development.