Role of the ATP-dependent chromatin-remodeling enzyme BRG1 in inner ear morphogenesis

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 DESCRIPTION (provided by applicant): The goal of this project is to characterize regulatory networks that drive neurosensory precursor cell development and differentiation in the inner ear. Specification and proliferation of otic epithelial precursor cells and the decision to become distinct cell types are crucial events during inner ear development. The instructions for these processes are encoded in the genome - in non-coding regulatory sequences. These control gene expression programs in time and space by interacting with transcription factors, cofactors and chromatin regulators to create and maintain specific cell states. Although many important genes have been identified in the inner ear, the network of factors and gene interactions that dictate the specialized phenotypes of differentiated cells during inner ear development are not understood. We found that the chromatin remodeling protein BRG1, the central enzymatic subunit in the SWI/SNF chromatin remodeling machinery, is necessary for initiating neuronal developmental program by interacting with inner ear neurosensory cell-specific transcription factors EYA1 and SIX1 in gain-of-function studies in cochlear explants and 3T3 fibroblast cells. However, no studies have yet been performed to directly address the developmental roles of SWI/SNF chromatin remodelers in the inner ear. While chromatin remodelers provide an important mechanism for gene transcription, the DNA regulatory elements/enhancers that regulate inner ear development and function are not defined. Our preliminary data clearly show that Brg1 plays a critical role in inner ear morphogenesis. In this application, we propose to define the developmental roles of Brg1 in neurosensory precursor cell development and differentiation and address whether Brg1 defines enhancers required to promote neuronal and sensory cell identity. The experiments proposed in this study have the potential to provide new insight into how a network of factors and gene interactions constitute the program that drives otic epithelial cell development towards functional sensory neurons or hair cells. Identifying genes and regulatory networks that control sensory or neuronal-cell specific gene expression program should provide valuable insights into the genetic networks that underlie congenital neurosensory deficits.