Chromatin-based regulation of neural stem cells

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Neural stem cells (NSCs) hold promise for the treatment of a wide range of neurological disorders common to Veterans such as traumatic brain injury (TBI) and Parkinson’s disease. In addition to providing cells for transplantation-based therapies, NSCs are also an important source of human neurons and glia for drug discovery and development. To realize the full potential of NSCs for human therapy, it is important to understand the molecular mechanisms that regulate the production of specific neural cell types. Our long-term goal is to understand the cellular and molecular mechanisms by which NSCs produce specific types of neurons and glia. The postnatal and adult mammalian brain harbors NSCs in the ventricular-subventricular zone (V-SVZ). Importantly, V-SVZ NSCs retain distinct regional identities that dictate the production of different neuronal subtypes. For instance, NSCs in the ventral V-SVZ produce neuron subtypes different from those born from NSCs in the dorsal V-SVZ. How NSCs “remember” their regional identity has been unclear. Mixed lineage leukemia-1 (Mll1) encodes a chromatin regulator that is part of an evolutionarily conserved transcriptional memory system, and MLL1 is required for normal V-SVZ neurogenesis. Recently, we showed that MLL1 is required for the maintenance of NSC regional identity. Even transient inhibition of MLL1 activity causes ventral NSCs to “forget” their regional identity and generate neurons more typical of dorsal NSCs. This change in developmental potential with transient MLL1 inhibition corresponds to persistent changes at the level of the transcriptome and chromatin-state. The objective of this proposal is to understand the role of MLL1 in maintaining NSC identity. Based on Preliminary Studies and our previously published data, our central hypothesis is that MLL1 is required to maintain NSC identity via specific changes to chromatin architecture. In this renewal application, we propose to investigate the function of MLL1 in maintaining key aspects of NSC identity. Given that NSC identity is a critical aspect of their neurogenic potential, results obtained will have important implications for our ability to produce specific types of neurons for human translational research and transplantation therapies. The proposed studies may inform methods in which transient MLL1-inhibition is used to broaden the developmental potential of NSC populations by “erasing” their regional and temporal identity. Furthermore, these studies advance new basic, neurodevelopmental concepts regarding NSC identity, which may be important to understanding how mutations in human MLL1 cause Weidemann-Steiner Syndrome, a developmental disorder that includes intellectual disability and autism. Finally, discovering MLL1-dependent mechanisms at genomic regulatory elements will likely be of interest to the broader fields of neurodevelopment, epigenetics and stem cell biology. Our published results, Preliminary Studies, and expertise in V-SVZ and chromatin biology support the feasibility of these Aims.