Novel epigenetic mechanisms in neuronal development and cognitive function

神经元发育和认知功能的新表观遗传机制

基本信息

批准号：
8527849
负责人：
Yang Shi
金额：
$ 45.48万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-10 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8527849
关键词：
Ablation Address Affect Alleles Amygdaloid structure Area Astrocytes Attention Behavior Behavioral Binding Sites Biochemical Biology Brain Candidate Disease Gene ChIP-seq Chromatin Cognition Cognitive Cognitive deficits Collaborations Commit Country DNA Methylation Data Data Set Defect Dendrites Dendritic Spines Development Diagnosis Disease Emotional Enhancers Epigenetic Process Future Gene Expression Gene Targeting Generations Genes Genetic Transcription Genomics Goals Growth Hippocampus (Brain)Histone H3 Histones Human Human Genetics Impaired cognition Individual Intelligence quotient Investigation Knockout Mice Lead Learning Light Location Long-Term Potentiation Lysine Medial Mediating Memory Memory impairment Mental Depression Mental Retardation Methylation Modeling Modification Molecular Molecular Abnormality Molecular Mechanisms of Action Morphology Mus Mutant Strains Mice Mutate Mutation Neurobiology Neurologic Neurons Nucleic Acid Regulatory Sequences Organism Patients Pattern Phenotype Physiology Play Population Prefrontal Cortex Process Proteins Proteomics Regulation Role Structure Synapses Synaptic plasticity Testing Therapeutic Intervention Visual X-linked mental retardation 3 Yang base chromatin modification cognitive function conditioned fear demethylation genome-wide histone modification human disease in vivo insight long term memory mouse model neurodevelopment neuron development novel promoter research study trait transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Mental retardation (MR) is a pathological condition diagnosed by a low intelligence quotient (IQ<70). MR affects 2-3% of the total population and is considered one of the most costly diseases in Western countries. Although human genetic studies have identified a plethora of MR candidate genes whose protein products are implicated in diverse neuronal processes, mechanisms by which many of these MR candidate genes regulate cognitive functions remain largely unclear. Epigenetic regulation has recently emerged as a potentially crucial mechanism in MR. Epigenetic regulation utilizes chromatin modifications (DNA methylation and histone covalent modifications) to produce stable changes in gene transcriptional activity, which impact development and physiology of the organism. We recently identified and characterized two histone demethylases, SMCX and PHF8, both causing mental retardation when mutated in humans, suggesting an important role for histone methylation dynamics in human cognitive function. Importantly, we have recently generated mice carrying a conditional allele of Smcx. Ablation of Smcx in the brain causes cognitive defects in associative memory and reduced expression of genes regulated by neuronal activity in amygdala. One of the main goals of this application is to understand the cellular and molecular mechanism of action of Smcx in learning and memory. Specifically, we will investigate if Smcx plays a general role in the formation of various memories, including short versus long term memory. We will investigate the cellular basis for the memory deficits associated with Smcx loss. Specifically, we will determine whether loss of Smcx impacts neural development as well as synaptic/dendritic structure and function. We will also carry out electrophysiological studies to determine the impact of Smcx loss on long-term potentiation and depression. These experiments will provide novel insights into the cellular mechanism by which Smcx regulates memory formation. We will also investigate the molecular mechanism by which Smcx regulates learning and memory. We will address this question by identifying, at genome-wide level, Smcx binding sites and gene expression networks regulated by Smcx. Based on our preliminary data, special attentions will be given to enhancers where Smcx may contribute to the generation of H3K4me1 (a defining histone modification with unclear functional role) via its demethylase activity and thus contribute to activity-dependent neuronal gene transcription during memory formation. Findings will not only provide significant molecular insights into how SMCX regulates cognition but also shed light on the functional role of H3K4me1 at enhancers, which remained an outstanding question in the epigenetic field. Taken together, the proposed studies will provide significant new insights into epigenetic mechanisms that control cognitive function and behavior, and, when go awry, cause debilitating human diseases such as MR.

描述（申请人提供）：精神发育迟滞（MR）是一种以低智商（IQ<70）诊断的病理状况。 MR 影响总人口的 2-3%，被认为是西方国家代价最高的疾病之一。尽管人类遗传学研究已经确定了大量的 MR 候选基因，其蛋白质产物与不同的神经元过程有关，但这些 MR 候选基因中的许多调节认知功能的机制仍不清楚。表观遗传调控最近已成为 MR 中潜在的关键机制。表观遗传调控利用染色质修饰（DNA 甲基化和组蛋白共价修饰）来产生基因转录活性的稳定变化，从而影响生物体的发育和生理学。我们最近鉴定并表征了两种组蛋白去甲基化酶 SMCX 和 PHF8，这两种酶在人类中发生突变时都会导致智力低下，这表明组蛋白甲基化动态在人类认知功能中发挥着重要作用。重要的是，我们最近培育出了携带 Smcx 条件等位基因的小鼠。大脑中 Smcx 的消融会导致联想记忆的认知缺陷，并减少杏仁核神经元活动调节的基因表达。该应用的主要目标之一是了解 Smcx 在学习和记忆中的细胞和分子作用机制。具体来说，我们将研究 Smcx 是否在各种记忆的形成中发挥一般作用，包括短期记忆和长期记忆。我们将研究与 Smcx 丢失相关的记忆缺陷的细胞基础。具体来说，我们将确定 Smcx 的丢失是否会影响神经发育以及突触/树突结构和功能。我们还将进行电生理学研究，以确定 Smcx 缺失对长时程增强和抑制的影响。这些实验将为 Smcx 调节记忆形成的细胞机制提供新的见解。我们还将研究 Smcx 调节学习和记忆的分子机制。我们将通过在全基因组水平上识别 Smcx 结合位点和 Smcx 调控的基因表达网络来解决这个问题。根据我们的初步数据，将特别关注增强子，其中 Smcx 可能通过其去甲基酶活性促进 H3K4me1（一种功能作用不明确的定义组蛋白修饰）的生成，从而有助于记忆形成过程中依赖于活动的神经元基因转录。研究结果不仅将为 SMCX 如何调节认知提供重要的分子见解，还将阐明 H3K4me1 在增强子中的功能作用，这仍然是表观遗传学领域的一个突出问题。总而言之，拟议的研究将提供重要的新见解控制认知功能和行为的表观遗传机制，一旦出现问题，就会导致诸如 MR 等使人衰弱的人类疾病。