Characterization of the role of CpA methylation in neuronal plasticity

CpA 甲基化在神经元可塑性中作用的表征

• 批准号: 7852463
• 负责人: Stavros Lomvardas
• 金额: $ 231.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7852463
• 关键词: Accounting; Axon; Brain; Chromatin; Clinical; CpG Islands; DNA; DNA Methylation; Data; Dementia; Dinucleoside Phosphates; Environment; Epigenetic Process; Gene Expression; Gene Silencing; Genes; Genetic Transcription; Long-Term Potentiation; Mediating; Medical; Methods; Methylation; Modification; Neurodevelopmental Disorder; Neurologic; Neuronal Plasticity; Neurons; Process; Research; Role; Specificity; Synapses; Synaptic plasticity; abstracting; autism spectrum disorder; experience; genome-wide; novel; public health relevance; research study; socioeconomics; transcription factor

DESCRIPTION (Provided by the applicant) Abstract: Our brain displays an astonishing degree of plasticity. Experiences from a constantly changing environment generate, modify and eliminate synapses and alter the function of our neurons. Extensive research over the last three decades has demonstrated that long term potentiation is a process that requires enduring changes in gene expression. Although transcription factors mediate most of these changes, it is the covalent modifications on DNA and chromatin that render this changes long lasting. Among these, "so called" epigenetic changes, DNA methylation is the only one that cannot be enzymatically reversed. DNA methylation on CpG islands is a well established mechanism of gene silencing. Here, we show that we discovered a novel epigenetic modification, the methylation of CpA dinucleotides. Using a novel, genome-wide method to detect CpA methylation in primary neurons, we made the remarkable observation that CpA methylation appears only on actively transcribed genes. Moreover, our preliminary data suggest that this modification can be modulated by neuronal activity; exactly like the transcription status of the genes that it marks. An irreversible modification that can enhance, or modulate gene expression could have profound consequences in neuronal plasticity. Therefore, we propose experiments that will dissect the role of CpA methylation in gene expression and neuronal function. Public Health Relevance: In this proposal we describe a novel epigenetic modification, the activity dependent methylation of CpA dinucleotides in primary neurons. We propose experimental strategies that will reveal the role of this modification in gene expression and neuronal function. CpA methylation, as a regulatory mechanism, could have critical impact on a plethora of neuronal functions, including axon targeting and synaptic plasticity and specificity. Taken into account that DNA methylation is pharmacologically amenable, our findings could have significant clinical consequences. A large spectrum of neurological or neurodevelopmental disorders, ranging from dementia to autism spectrum disorders, could be caused by the inability of a neuron to transform synaptic activity into long lasting changes in gene expression. Therefore, understanding the role of this epigenetic modification in this process should have a broad scientific, medical and socioeconomic effect.

描述（申请人提供） 摘要：我们的大脑显示出惊人的可塑性程度。不断变化的环境的经验会产生，修改和消除突触并改变神经元的功能。在过去的三十年中，广泛的研究表明，长期增强是一个需要持久基因表达变化的过程。尽管转录因子介导了大多数这些变化，但DNA和染色质的共价修饰使这种变化变化了持久。其中，“所谓的”表观遗传变化，DNA甲基化是唯一无法酶逆转的甲基化。 CpG岛上的DNA甲基化是基因沉默的良好机制。在这里，我们表明我们发现了一种新型的表观遗传修饰，即CPA二核苷酸的甲基化。我们使用一种新型的全基因组方法检测原发性神经元中的CPA甲基化，我们对CPA甲基化仅出现在主动转录的基因上。此外，我们的初步数据表明，这种修饰可以通过神经元活动来调节。就像它标记的基因的转录状态一样。可以增强或调节基因表达的不可逆修饰可能对神经元可塑性产生深远的影响。因此，我们提出的实验将剖析CPA甲基化在基因表达和神经元功能中的作用。 公共卫生相关性：在此提案中，我们描述了一种新型的表观遗传修饰，这是原发性神经元中CPA二核苷酸的活性甲基化。我们提出的实验策略将揭示这种修饰在基因表达和神经元功能中的作用。作为调节机制，CPA甲基化可能对众多神经元功能产生关键影响，包括轴突靶向和突触可塑性和特异性。考虑到DNA甲基化在药理学上是可正常的，我们的发现可能会产生重大的临床后果。从痴呆到自闭症谱系障碍的大量神经或神经发育障碍可能是由于神经元无法将突触活性转化为基因表达持续变化的持续变化而引起的。因此，了解这种表观遗传修饰在此过程中的作用应具有广泛的科学，医学和社会经济效应。