Chromatin Remodeling and Memory Storage

描述（由申请人提供）：长期以来，人们已经认识到基因转录是长期记忆储存所必需的，但直到最近才清楚的是，记忆过程的转录调节涉及与染色质（一种包装DNA的蛋白质复合物）相互作用的多种转录因子和共激活因子的协同作用。染色质最初被认为是静态的和结构性的，现在已知是非常动态的，对基因表达施加精确的控制。染色质重塑可能调控记忆过程中的基因表达的想法最近通过对参与染色质重塑的酶，特别是组蛋白乙酰转移酶（HAT）和组蛋白脱乙酰酶（HDAC）的研究获得了相当大的关注。例如，我们之前的研究表明CREB结合蛋白（CBP），一种有效的HAT和转录共激活因子，对于突触可塑性（神经元连接强度的活性依赖性变化）和长期记忆的持久形式至关重要。在这个拟议的研究计划中，我们将继续研究我们的中心假设，即参与染色质重塑的酶对参与记忆过程的基因表达至关重要。我们的初步数据表明，HDAC抑制剂（小分子拮抗剂，阻断HDAC活性和诱导组蛋白超乙酰化状态）增强突触可塑性和记忆储存。此外，我们发现HDAC抑制剂通过确定的分子机制增强记忆过程。为了研究HDAC抑制剂对记忆储存的影响，并确定HDAC抑制剂调节记忆储存的分子机制，我们提出了三个具体的目标。在具体目标1中，我们将研究HDAC抑制如何影响记忆。在具体目标2中，我们将定义HDAC抑制增强记忆的潜在分子机制。在具体目标3中，我们将研究染色质重塑如何调节记忆巩固过程中的基因表达。这些实验的结果有望大大有助于我们理解染色质重塑如何通过组蛋白修饰调节基因表达所需的持久形式的记忆。染色质重塑被认为是“表观遗传”调控的一种形式，其中基因表达在不改变DNA密码的情况下受到调控，并且可能具有持久的影响。神经元基因调控的持续表观遗传机制最近已成为几种认知障碍，包括精神发育迟滞，抑郁症和精神分裂症的核心。 公共卫生相关性：很明显，记忆过程的转录调控涉及多个转录因子和与染色质（一种包装DNA的蛋白质复合物）相互作用的共激活因子的协同作用。染色质重塑被认为是一种“表观遗传”调控形式，其中基因表达在不改变DNA密码的情况下受到调控，并且可能具有持久的影响，这一想法已成为理解包括精神发育迟滞、抑郁症和精神分裂症在内的几种认知障碍的分子机制的核心。这项研究计划中的实验重点是了解染色质重塑如何调节记忆过程所需的基因表达。

DESCRIPTION (provided by applicant): It has long been appreciated that gene transcription is required for long-term memory storage, but only recently has it become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Originally thought to be static and structural in purpose, chromatin is now known to be very dynamic, exerting precise control over gene expression. The idea that chromatin remodeling may regulate gene expression for memory processes has gained considerable attention recently through the study of enzymes that are involved in chromatin remodeling, in particular, histone acetyltransferases (HATs) and histone deacetylases (HDACs). For example, our previous research demonstrated that CREB-binding protein (CBP), a potent HAT and transcriptional coactivator, is critical for long-lasting forms of synaptic plasticity (the activity- dependent change in the strength of neuronal connections) and long-term memory. In this proposed research program, we continue to examine our central hypothesis that enzymes involved in chromatin remodeling are essential for gene expression involved in memory processes. Our preliminary data demonstrate that HDAC inhibitors (small molecule antagonists that block HDAC activity and induce a histone hyper-acetylated state) enhance synaptic plasticity and memory storage. Further, we find that HDAC inhibitors enhance memory processes via a defined molecular mechanism. To examine the effect of HDAC inhibitors on memory storage and define the molecular mechanism underlying the modulation of memory storage by HDAC inhibitors we propose three specific aims. In specific aim 1, we will examine how HDAC inhibition affects memory. In specific aim 2, we will define the underlying molecular mechanism by which HDAC inhibition enhances memory. In specific aim 3, we will examine how chromatin remodeling regulates gene expression during memory consolidation. Results from these experiments promise to significantly contribute to our understanding of how chromatin remodeling via histone modification regulates gene expression required for long-lasting forms of memory. Chromatin remodeling is considered a form of `epigenetic' regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects. Sustained epigenetic mechanisms of gene regulation in neurons have recently become central to several cognitive disorders including mental retardation, depression, and schizophrenia. PUBLIC HEALTH RELEVANCE: It has become clear that transcriptional regulation for memory processes involves the concerted action of multiple transcription factors and coactivators that interact with chromatin, a protein complex that packages DNA. Chromatin remodeling is considered a form of `epigenetic' regulation, in which gene expression is regulated without altering the DNA code, and may have long-lasting effects, an idea that has become central to understanding the molecular mechanisms underlying several cognitive disorders including mental retardation, depression, and schizophrenia. The experiments in this research proposal are focused on understanding how chromatin remodeling regulates gene expression required for memory processes.