Role of nucleosome composition and histone variant exchange in associative learning and memory

核小体组成和组蛋白变体交换在联想学习和记忆中的作用

• 批准号: RGPIN-2015-05115
• 负责人: Zovkic, Iva
• 金额: $ 2.4万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684999
• 关键词: Role; nucleosome; composition; histone; variant

Memory formation is a process in which fleeting events produce lasting outcomes by altering gene expression. Mechanisms by which the environment affects genes is not well understood, but it involves epigenetic modifications of histone proteins H2A, H2B, H3, and H4, which regulate access to DNA. My work is focused on understanding how histones regulate access to DNA as a method for understanding how memories form. We recently identified histone variants, which replace existing histones and alter access to DNA, as a novel epigenetic regulator of memory. Specifically, we found that H2A.Z, a variant of histone H2A, is an epigenetic factor that suppress memory through an unknown mechanism. Given its pervasive expression and relevance for memory, we will focus on mechanisms of H2A.Z regulation as an essential step in elucidating the role of histones in mediating lasting changes in behaviour.***          H2A.Z has contradictory effects on gene activity and understanding the factors that modify its function is critical for uncovering the basis for its role in memory. Here, we will determine whether Anp32e, a novel regulator of H2A.Z, controls its removal from particular positions to increase gene activity and promote memory. This work will be the first to investigate how histones are regulated at some positions and not others, an essential step in diagraming the mechanism by which histones regulate experience-induced gene activity.***          Effects of H2A.Z on gene activity are also influenced by modifying H2A.Z with ubiquitin. How this modification impacts gene activity during learning is not known and proposed studies will elucidate its function in memory. We will focus specifically on ubiquitinated H2A.Z as a filter that modifies how strong a stimulus needs to be to initiate information storage and maintenance as memory. This work will be essential for detangling the complexity of H2A.Z function by identifying the factors that influence when H2A.Z is permissive or restrictive for gene expression, and ultimately, for memory formation.***          Finally, we will investigate how H2A.Z integrates with classical mechanisms of memory. Only some cells within a brain region encode a given memory and selecting which cells participate is a competitive process that is positively regulated by memory-promoting genes. Here, we will determine if H2A.Z, a memory suppressor, confers a competitive disadvantage for incorporating cells into memory. This work will provide first insights into epigenetic regulation of cell assemblies and a much needed bridge between epigenetic actions in the nucleus and classical mechanisms of memory.***          Overall, this work will produce highly visible research that will advance H2A.Z knowledge across disciplines focused on gene regulation. In particular, this work will transform our understanding of factors that fine-tune gene activity in response to external stimuli to regulate lasting changes in behaviour.**

记忆的形成是一个过程，在这个过程中，短暂的事件通过改变基因表达产生持久的结果。环境影响基因的机制尚不清楚，但它涉及组蛋白H2A，H2B，H3和H4的表观遗传修饰，这些蛋白调节DNA的访问。我的工作重点是了解组蛋白如何调节DNA的访问，作为理解记忆如何形成的方法。我们最近发现组蛋白变体，取代现有的组蛋白和改变DNA的访问，作为一种新的记忆表观遗传调节因子。具体来说，我们发现组蛋白H2A的一种变体H2A.Z是一种表观遗传因子，通过一种未知的机制抑制记忆。鉴于其普遍表达和记忆的相关性，我们将重点关注H2A.Z调节的机制，作为阐明组蛋白在介导持久行为变化中的作用的重要步骤。 H2A.Z对基因活性有矛盾的影响，了解改变其功能的因素对于揭示其在记忆中作用的基础至关重要。在这里，我们将确定Anp32e，一种新的H2A.Z调节剂，是否控制其从特定位置的去除，以增加基因活性和促进记忆。这项工作将是第一个研究组蛋白如何在某些位置而不是其他位置受到调节的工作，这是重新阐明组蛋白调节经验诱导的基因活性的机制的重要一步。* H2A.Z对基因活性的影响也受到用泛素修饰H2A.Z的影响。这种修饰在学习过程中如何影响基因活性尚不清楚，拟议的研究将阐明其在记忆中的功能。我们将特别关注泛素化的H2A.Z作为一种过滤器，它可以改变刺激需要多大的强度来启动信息存储和维持记忆。这项工作对于通过确定影响H2A.Z何时允许或限制基因表达并最终形成记忆的因素来解开H2A.Z功能的复杂性至关重要。 最后，我们将研究H2A.Z如何与经典的记忆机制相结合。只有大脑区域内的一些细胞编码给定的记忆，选择哪些细胞参与是一个由记忆促进基因积极调控的竞争过程。在这里，我们将确定是否H2A.Z，一种记忆抑制剂，赋予将细胞纳入记忆的竞争劣势。这项工作将首次深入了解细胞组装的表观遗传调控，以及细胞核中的表观遗传作用与经典记忆机制之间急需的桥梁。 总的来说，这项工作将产生高度可见的研究，将推进跨学科的H2A.Z知识集中在基因调控。特别是，这项工作将改变我们对微调基因活性以响应外部刺激的因素的理解，以调节行为的持久变化。