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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：
8371566
负责人：
Yang Shi
金额：
$ 51.01万
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/8371566
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 RNA 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

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. PUBLIC HEALTH RELEVANCE: This application studies epigenetic mechanisms that regulate neuronal development and cognitive function. When these mechanisms go awry, they can lead to debilitating human disease such as mental retardation. Findings from the proposed studies will lay important conceptual frameworks for future therapeutic intervention.

描述（由申请人提供）：精神发育迟滞（MR）是一种由低智商（IQ<70）诊断的病理状态。MR影响总人口的2-3%，被认为是西方国家最昂贵的疾病之一。虽然人类遗传学研究已经确定了大量的MR候选基因，其蛋白质产物涉及不同的神经元过程，这些MR候选基因中的许多调节认知功能的机制仍然很大程度上不清楚。表观遗传调控是近年来出现的一种重要的MR调控机制。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）使基因转录活性发生稳定变化，从而影响生物体的发育和生理。我们最近发现并表征了两种组蛋白去甲基化酶SMCX和PHF 8，它们在人类中突变时都会导致智力迟钝，这表明组蛋白甲基化动力学在人类认知功能中起着重要作用。重要的是，我们最近产生了携带Smcx条件等位基因的小鼠。大脑中Smcx的消融导致联想记忆中的认知缺陷和杏仁核中神经元活动调节的基因表达减少。本申请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，包括短期与长期记忆。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丢失对长时程增强和抑郁的影响。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确定Smcx结合位点和Smcx调控的基因表达网络来解决这个问题。基于我们的初步数据，将特别关注Smcx可能通过其去甲基化酶活性促进H3 K4 me 1（一种功能作用不明确的定义性组蛋白修饰）生成的增强子，从而促进与记忆形成过程中活动依赖的神经元基因转录有关。这些发现不仅将为SMCX如何调节认知提供重要的分子见解，还将揭示H3 K4 me 1在增强子中的功能作用，这仍然是表观遗传学领域的一个悬而未决的问题。总之，拟议的研究将提供重要的新见解进入控制认知功能和行为的表观遗传机制，当出错时，会导致使人衰弱的疾病，如MR。公共卫生相关性：该应用程序研究调节神经元发育和认知功能的表观遗传机制。当这些机制出错时，它们可能导致使人衰弱的疾病，如智力迟钝。从拟议的研究结果将奠定重要的概念框架，为未来的治疗干预。