Epigenetic Mechanisms of Gene Regulation in Long-Term Memory Formation

通过一个称为记忆的过程，新获得的内存变得稳定，可以长期存储 整合，这需要从头开始表达基因。在这一过程中基因转录的中断 特别是阻止长期记忆的形成。Braln相关的神经营养因子(BDNF)已被 被证明在巩固或存储长期记忆方面起着至关重要的作用。然而，人们对此知之甚少 关于大脑中外显子特异性ibc/nf转录本的调控以及这种水平的脑源性神经营养因子是如何调节的 在记忆形成过程中的作用。这项提议的主要科学目标是确定 用于长期稳定的/bofn？gerie表达变化的表观遗传调节机制 记忆。这项授权的基本假设是，异常的表观遗传标记，如翻译后 组蛋白修饰、DNA甲基化和转录因子激活在 记忆形成过程中外显子特异的脑源性神经营养因子基因调控。本建议书的指导阶段将剖析 记忆巩固过程中外显子特异性Mn？基因调控的表观遗传学机制 包括测量与外显子特异性BDNF相关的DNA甲基化的方法的组合 转录本，使用染色质免疫沉淀(芯片)技术分析翻译后水平 Tiofnf启动子区组蛋白、甲基CpG结合蛋白2和组蛋白去乙酰基酶的修饰， 以及研究DNMT抑制是否改变记忆过程中6c/nf外显子特异性的mRNA表达 整合。在该项目的第一个独立阶段目标中，NMDA受体(NMDA-R)的作用 将使用一种新的组合来分析BDNF基因表观遗传调控的激活 评估海马区M/IF转录本的细胞类型特异性染色质重塑的技术。这个 第二独立阶段AIM将评估NMDA-R干预的招募的功能影响 转录因子核因子kappaB(NF-KB)到DNA中的/BC/nf调控元件，并鉴定 核因子-kB DNA结合复合体在调节BDNF基因染色质重构中的作用。本研究探讨脑源性神经营养因子基因调控的表观遗传学机制在长期记忆形成中的作用，重点探讨可能导致药物发现和开发的分子机制，以干预精神障碍的临床特征。事实上，表观遗传机制与精神疾病的病因学有关，如精神分裂症、抑郁症和双相情感障碍。通过了解记忆过程中涉及/bofnf基因表达的表观遗传调控机制 形成和潜在的精神障碍，参与这一过程的其他基因可能属于共同的 可进行疾病干预的生化途径

newly acquired memory becomes stable for long-term storage through a process known as memory consolidation, which requires de novo gene expression. Disruption of gene transcription during this process specifically blocks long-term memory formation. The braln-derlved neurotrophic factor (BDNF) has been shown to play an essential role in the consolidation or storage of long-term memory. However, little is known about the regulation of exon-specific ibc/nf transcripts in the brain and how this level of bdnf ger\e regulation functions in the process of memory formation. The major scientific goal of this proposal is to identify epigenetic-regulating mechanisms for /bofn^gerie expression changes that serve to stabilize long-term memory. The underlying hypothesis of this grant Is that aberrant epigenetic markings such as posttranslational modification of histones, DNA methylation and transcription factor activation plays a role in exon-specific bdnf gene regulation in memory formation. The mentored phase ofthis proposal will dissect epigenetic mechanisms of exon-specific Mn?gene regulation during memory consolidation using a combination of approaches including measuring DNA methylation associated with exon-specific bdnf transcripts, using chromatin immunoprecipition (ChIP) technology to analyze levels of post-translational modification of histones, methyl CpG binding protein 2, and histone deacetylases at tiofnf promoter regions, and investigating whether DNMT inhibition alters 6c/nf exon-specific mRNA expression during memory consolidation. During the first independent phase aim ofthe project, the role for NMDA receptor (NMDA-R) activation in the epigenetic regulation ofthe bdnf gene will be analyzed using a combination of novel technologies to assess cell-type specific chromatin remodeling of M/if transcripts in hippocampus. The second Independent phase aim will evaluate the functional Impact of NMDA -R-medlated recruitment ofthe transcription factor nuclear factor kappa B (NF-KB) to /bc/nf regulatory elements within DNA and to identify the role ofthe NF-KB DNA-binding complex in the regulation of chromatin remodeling ofthe bdnf gene. This proposal explores the role of epigenetic mechanisms of bdnf ger\e regulation In long-term memory formation with a focus on identifying molecular mechanisms that may lead to drug discovery and development to intervene in the ciinicai features of mental disorders. Indeed, epigenetic mechanisms have been implicated in the etiology of mental illnesses, such as schizophrenia, depression, and bipolar disorder. Through the understanding of epigenetic-regulating mechanisms involved in /bofnf gene expression during memory formation and potentially in mental disorders, other genes involved in this process may fall into a common biochemical pathway where disease intervention Is possible