Cell-Specific PRC1 Accessory Proteins and the Regulation of Mammalian Neurodevelopment

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Mammalian embryonic development is the process whereby a single naïve cell is expanded, and serially specialised, to produce all of the functional cell types of the adult body. This intricate process is governed by proteins, which bind to regulatory DNA sequences and establish the appropriate temporal and spatial patterns of gene expression. One such family of protein effectors form multi-subunit-assemblies termed polycomb repressive complexes (PRCs), which function to block gene expression by chemically and physically modifying chromatin - the packaged form of DNA. In the developing brain, changes in cell state occur as progenitor cells proliferate, migrate and specialise, and PRCs have been shown to be important for these steps. Consequently, loss of PRC function in this context leads to cellular and structural abnormalities. Weaver syndrome, a disorder characterised by cognitive impairment and often brain overgrowth, is caused by the loss of PRC function. Moreover, mutations that block PRC activity occur in the majority of cases of diffuse intrinsic pontine glioma (DIPG) in which they promote tumour formation. PRCs are also required for the regulation of cell proliferation, specialisation and protection against neurodegeneration in the adult brain. Mechanistic interpretation of these cellular and structural abnormalities, however, is hindered by the lack of understanding of how PRCs regulate neurodevelopmental gene expression patterns. Filling this knowledge gap is key to understanding not only the molecular basis of brain development, but also in determining the underlying deficits in developmental brain disorders. To this end, it is important to determine the molecular mechanics of PRC function and targeting during neurodevelopment. My key aims are: 1). Determine the extent and functional importance of alterations in PRC complex composition during neurodevelopment. 2). Identify and manipulate proteins which act either directly, or in collaboration with chromatin modifications, to recruit PRCs to their target genes during neurodevelopment. To address these aims I will utilise artificially differentiated and primary cultured neural progenitor cells (NPCs) in conjunction with high-throughput analysis of chromatin state, quantitative analysis of protein composition of PRC bound chromatin, genome-engineering and synthetic protein targeting approaches. A complete understanding of the molecular basis of disorders of the brain which arise from PRC dysfunction will be critical as a step towards establishing effective and safe therapeutic approaches, prognostic and diagnostic tests and to inform clinical support.