Chromatin-based regulation of neural stem cells

神经干细胞（NSCs）有望用于治疗各种神经系统疾病 常见于退伍军人，如创伤性脑损伤（TBI）和帕金森病。除了提供细胞 对于基于移植的疗法，NSC也是用于药物治疗的人类神经元和神经胶质的重要来源。 发现和发展。为了充分发挥神经干细胞在人类治疗中的潜力，重要的是要了解 调节特定神经细胞类型产生的分子机制。我们的长期目标是 了解神经干细胞产生特定类型神经元和神经胶质的细胞和分子机制。 出生后和成年哺乳动物脑内的神经干细胞在脑室-脑室下区（V-SVZ）。 重要的是，V-SVZ神经干细胞保留了独特的区域特征，决定了不同神经元的产生 亚型例如，腹侧V-SVZ中的神经干细胞产生的神经元亚型不同于来自 背侧V-SVZ中的神经干细胞。NSC如何“记住”他们的区域身份一直不清楚。混合谱系 白血病-1（Mll 1）编码一种染色质调节因子，它是一种进化上保守的转录调控因子的一部分。 MLL 1是正常V-SVZ神经发生所必需的。最近，我们发现MLL 1是 这是维护国家安全委员会区域特性所必需的。即使是MLL 1活性的短暂抑制也会引起腹侧 神经干细胞“忘记”他们的区域身份，并产生更典型的背侧神经干细胞的神经元。的这种变化 具有短暂MLL 1抑制的发育潜力对应于在细胞水平的持续变化。 转录组和染色质状态。本提案的目的是了解MLL 1在以下方面的作用： 维护国家安全委员会的身份。根据初步研究和我们以前发表的数据，我们的中心 假设MLL 1是通过染色质结构的特异性改变来维持NSC身份所必需的。在 在这次更新申请中，我们建议研究MLL 1在维持国家安全委员会关键方面的功能 身份鉴于NSC的身份是其神经原性潜力的一个关键方面，所获得的结果将具有 对我们为人类转化研究生产特定类型神经元的能力具有重要意义， 移植疗法拟议的研究可能为使用瞬时MLL 1抑制的方法提供信息 通过“消除”他们的区域和时间特征来扩大NSC人口的发展潜力。 此外，这些研究提出了关于NSC身份的新的基本神经发育概念， 可能对理解人类MLL 1突变如何导致Weidemann-Steiner综合征很重要， 发育障碍，包括智力障碍和自闭症。最后，发现MLL 1依赖性 基因组调控元件的机制可能会引起更广泛的神经发育领域的兴趣， 表观遗传学和干细胞生物学。我们已发表的结果、初步研究和V-SVZ方面的专业知识， 染色质生物学支持这些目标的可行性。

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.