Chromatin-based cellular memory in neural stem cells

描述(由申请人提供) 摘要：这项建议解决了表观遗传学、干细胞生物学和再生医学的两个基本问题，这两个问题与基于染色质的细胞记忆系统有关。1.在特定遗传位点上的染色质修饰是否可以预测神经干细胞在大脑发育期间和成年期分化潜能的进行性“限制”？2.在前体细胞群体中，细胞记忆系统能否在染色质水平上被部分“擦除”或“重置”，以扩大其发育潜力？这些研究应该会极大地促进我们对前体细胞如何“记住”它们的时间和位置身份的理解，并确定这种细胞记忆系统是否可以被操纵以用于新的治疗策略。影响的三个领域是：发育神经生物学，其结果揭示了神经元和神经胶质分化的表观遗传机制；再生医学，其获得的见解可能提出指定细胞命运的新方法；以及癌症生物学，其结果可能揭示某些染色质错乱如何促进脑瘤。首先，我们建议研究从胚胎到成年的神经干细胞连续体中染色质修饰的变化。我们提出的利用从大脑中急性分离的细胞的方法代表了当前基于细胞培养的研究的重大进步。要做到这一点，我们必须创新染色质研究的新的、综合的方法。我们还将使用新的和尚未被证实的方法来“重置”细胞身份的染色质记忆，目的是改变细胞的命运。鉴于这些关于细胞记忆的染色质基础和战略性表观遗传操作的想法是新的，并且相对未经检验，我们提案中的风险水平大大高于传统的研究人员拨款。我们希望从我们目前的研究着手，以扩大我们研究的影响，并探索干细胞生物学中细胞记忆的基本原理。 公共卫生相关性：神经干细胞有望治疗神经疾病，了解这些前体分化为神经元和神经胶质的表观遗传学机制可能是释放其治疗潜力的关键。通过在表观遗传学、干细胞生物学和再生医学的十字路口进行研究，我们可能会开发出用于细胞替代策略的“工程”细胞的新方法。此外，我们的研究可能导致发现染色质重塑中的错乱如何导致脑瘤的发展。

DESCRIPTION (Provided by the applicant) Abstract: This proposal addresses two fundamental questions at the crossroads of epigenetics, stem cell biology, and regenerative medicine that relate to the chromatin-based cellular memory system. 1. Do chromatin modifications at specific genetic loci predict the progressive "restriction" of differentiation potential that occurs in neural stem cells during brain development and into adulthood? 2. Can cellular memory systems be partially "erased" or "reset" at the chromatin level in precursor cell populations to broaden their developmental potential? These studies should greatly advance our understanding of how precursor cells "remember" both their temporal and positional identities as well as determine whether this cellular memory system can be manipulated for novel therapeutic strategies. Three areas of impact are: Developmental Neurobiology, where results shed light on epigenetic mechanisms of neuronal and glial differentiation; Regenerative Medicine, where insight gained may suggest novel methods of cell fate specification; and Cancer Biology, where results may reveal how certain chromatin derangements can promote brain tumors. First, we propose investigating the changes in chromatin modifications that occur along a neural stem cell continuum from the embryo and into adulthood. Our proposed methods utilizing cells acutely isolated from the brain represent a significant advancement upon current cell culture based studies. To accomplish this, we must innovate new, integrative approaches for chromatin study. We will also employ novel and as of yet unproven approaches to "reset" chromatin memory of cell identity with the purpose of altering cell fate. Given that these ideas concerning the chromatin basis of cellular memory and strategic epigenetic manipulation are new and relatively untested, the level of risk in our proposal is substantially higher than in traditional investigator grants. We wish to embark on this tangent from our current studies to broaden the impact of our research and explore fundamental principles of cellular memory in stem cell biology. Public Health Relevance: Neural stem cells hold promise for the treatment of neurological disorders, and understanding the epigenetic mechanisms by which these precursors differentiate into neurons and glia may be key to unlocking their therapeutic potential. By performing research at the crossroads of epigenetics, stem cell biology, and regenerative medicine, we may develop novel methods of "engineering" cells for cell replacement strategies. Furthermore, our studies may lead to discoveries of how derangements in chromatin remodeling can lead to the development of brain tumors.