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

记忆形成是一个过程，在这个过程中，短暂的事件通过改变基因表达来产生持久的结果。环境影响基因的机制尚不清楚，但它涉及组蛋白H_2A、H_2B、H_3和H_4的表观遗传修饰，它调节对DNA的访问。我的工作重点是理解组蛋白如何调节DNA的访问，作为一种理解记忆形成的方法。我们最近发现了组蛋白变体，它取代了现有的组蛋白并改变了对DNA的访问，是一种新的记忆表观遗传调节因子。具体地说，我们发现组蛋白H2A的变种H2A.Z是一种表观遗传因子，通过一种未知的机制抑制记忆。鉴于组蛋白的普遍表达和与记忆的相关性，我们将重点介绍组蛋白的调节机制，作为阐明组蛋白在调节行为持久变化中的作用的关键步骤。 研究发现，H2A.Z对基因活动有相互矛盾的影响，了解修改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H_2A.Z的一种新的调节子Anp32e是否控制其从特定位置的移除，以增加基因活性和促进记忆。这项工作将是第一次研究组蛋白在某些位置是如何调控的，而不是在其他位置是如何调控的，这是描绘组蛋白调节经验诱导的基因活动的机制的关键一步。 此外，H_2A.Z对基因活性的影响也受到泛素修饰H_2A.Z的影响。这种修饰如何影响学习过程中的基因活动尚不清楚，拟议中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作为过滤器，它改变了启动信息存储和作为记忆的维护所需的刺激强度。这项工作将是必不可少的，通过确定影响H_2A.Z何时允许或限制基因表达，并最终影响记忆形成的因素，从而理清H_2A.Z功能的复杂性。 最后，我们将研究H2A.Z如何与经典的记忆机制相结合。只有大脑区域中的一些细胞编码给定的记忆，选择哪些细胞参与是一个竞争过程，受到记忆促进基因的积极调控。在这里，我们将确定记忆抑制因子H2A.Z是否会在将细胞整合到记忆中带来竞争劣势。这项工作将提供对细胞组合的表观遗传调控的第一次洞察，以及在核中的表观遗传行为和经典记忆机制之间亟需的桥梁。 总体而言，这项工作将产生高度可见性的研究，这些研究将促进专注于基因调控的学科之间的H2A.Z知识。特别是，这项工作将改变我们对因素的理解，这些因素通过微调基因活动来响应外部刺激，以调节行为的持久变化。

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.