Chromatin Remodeling and Memory Storage

描述(申请人提供)：长期以来，人们一直认识到，基因转录是长期记忆存储所必需的，但直到最近，人们才清楚地知道，记忆过程的转录调控涉及多个转录因子和共激活因子的协同作用，这些转录因子和共激活因子与染色质相互作用，染色质是包装DNA的蛋白质复合体。染色质最初被认为是静态的和有结构的，现在已知是非常动态的，对基因表达施加精确的控制。最近，通过对参与染色质重塑的酶的研究，特别是组蛋白乙酰转移酶(HATS)和组蛋白去乙酰基酶(HDAC)的研究，染色质重塑可能调节记忆过程的基因表达的想法受到了相当大的关注。例如，我们之前的研究表明，CREB结合蛋白(CBP)是一种强大的HAT和转录共激活因子，对于持久形式的突触可塑性(神经元连接强度的活性依赖变化)和长期记忆至关重要。在这项拟议的研究计划中，我们继续检验我们的中心假设，即参与染色质重塑的酶对于参与记忆过程的基因表达是必不可少的。我们的初步数据表明，HDAC抑制剂(阻断HDAC活性并诱导组蛋白超乙酰化状态的小分子拮抗剂)可以增强突触的可塑性和记忆存储。此外，我们发现HDAC抑制剂通过一种明确的分子机制增强记忆过程。为了检测HDAC抑制剂对记忆存储的影响，并确定HDAC抑制剂调节记忆存储的分子机制，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抑制是如何影响记忆的。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。在特定的目标3中，我们将研究在记忆巩固过程中染色质重塑如何调节基因表达。这些实验的结果有望极大地有助于我们理解染色质重塑是如何通过组蛋白修饰来调节长期记忆所需的基因表达的。染色质重塑被认为是一种表观遗传调节，在这种调节中，基因的表达不会改变DNA密码，并可能具有长期的影响。神经元基因调控的持续表观遗传机制最近已成为包括智力低下、抑郁和精神分裂症在内的几种认知障碍的核心。 与公共健康相关：很明显，记忆过程的转录调控涉及多个转录因子和共激活因子的协同作用，这些转录因子和共激活因子与染色质相互作用，染色质是一种包装DNA的蛋白质复合体。染色质重塑被认为是一种表观遗传调控，在这种调控中，基因的表达不会改变DNA密码，可能会产生长期的影响，这一观点已经成为理解包括智力低下、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.