Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms of NSC neurogenesis and gliogenesis is key to unlocking their therapeutic potential. The adult brain - including that of humans - harbors a population of NSCs in the subventricular zone (SVZ). How NSCs 'forget'the epigenetic memory of their stem cell identity and 'learn'the developmental programs for neurogenesis and gliogenesis is poorly understood. Mll1 (Mixed lineage leukemia-1), a chromatin-remodeling factor related to Drosophila Trithorax, can regulate cellular identity by mediating the application or removal of specific chromatin modifications. We previously showed that Mll1 is required for the genesis of neurons - but not glial cells - from postnatal SVZ NSCs (Nature 2009, 458:529- 33). Emerging studies indicate that distinct chromatin signatures at DNA regulatory elements called enhancers determine the transcriptional activity of specific gene promoters, but little is known about how the chromatin-state at enhancers is regulated. In Preliminary Studies, we show that MLL1 promotes the expression of neurogenic genes Dlx2 and Dlx5 by regulating intergenic enhancer elements (manuscript submitted to Nature Cell Bio). Our chromatin analysis supports a model in which MLL1 maintains enhancers in a 'poised'state to facilitate rapid gene activation during neuronal differentiation. Furthermore, we found that MLL1 is required for the localization of JMJD3, a histone demethylase capable of removing repressive trimethylation of histone 3 at lysine 27 (H3K27me3) at poised enhancer elements. To investigate the role of JMJD3 in adult neurogenesis, we studied JMJD3-loss of function in vivo and in vitro with conditional knockout and shRNA-mediate knockdown. Indeed, JMJD3-deficient SVZ NSCs were defective for neurogenesis, but not gliogenesis. Based on these new data, we hypothesize that MLL1 coordinates neuronal differentiation from multipotent NSCs by targeting specific enhancer elements, enabling their rapid activation by the action of JMJD3. In this application, we propose Specific Aims that test this regulatory model, which has broad implications for development in general, and further determine the role of MLL1 in neural development.
Neural stem cells (NSCs) hold promise for the treatment of neurological disorders, and understanding the molecular mechanisms by which NSCs differentiate into neurons and glia is key to unlocking their therapeutic potential. Our goal is to determine the molecular mechanisms that regulate NSC biology. For NSCs to make neurons, daughter cells need to express certain sets of genes while repressing others. Such lineage-specific gene expression is in regulated by chromatin structure - the packaged state of DNA. Recent work in my lab demonstrated that the MLL1 chromatin remodeling factor is required for neuronal differentiation from NSCs. We plan to use cell biology and molecular approaches to investigate how MLL1 and related factors coordinate the production of neurons from NSCs. Data from these proposed studies may advance the development of cell-based therapies for service-related injuries as well as neurodegenerative diseases in our Veteran population.
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