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：
8925143
负责人：
Yang Shi
金额：
$ 47.37万
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 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925143
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 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 Genetic study 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 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 development cognitive function conditioned fear demethylation epigenetic regulation genome-wide histone demethylase histone methylation histone modification human disease in vivo insight long term memory mouse model neurodevelopment neuron development novel promoter research study trait transcriptome sequencing

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 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 Genetic study 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 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 development cognitive function conditioned fear demethylation epigenetic regulation genome-wide histone demethylase histone methylation histone modification human disease in vivo insight long term memory mouse model neurodevelopment neuron development novel promoter research study trait transcriptome sequencing

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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（由申请人提供）：智力低下（MR）是由低智力商诊断的病理状况（IQ <70）。 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。尽管人类遗传研究已经确定了许多MR候选基因，其蛋白质产物与多种神经元过程有关，但这些MR候选基因中许多调节认知功能的机制仍然在很大程度上不清楚。表观遗传调节最近已成为MR中潜在的至关重要的机制。表观遗传调节利用染色质修饰（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，这会影响生物体的发育和生理学。我们最近确定并表征了两个组蛋白脱甲基酶SMCX和PHF8，它们在人类中突变时会导致智力低下，这表明组蛋白甲基化动力学在人类认知功能中的重要作用。重要的是，我们最近产生了携带有条件的SMCX等位基因的小鼠。 SMCX在大脑中的消融会导致关联记忆的认知缺陷，并降低杏仁核神经元活性调节的基因表达。该应用程序的主要目标之一是了解SMCX在学习和记忆中的细胞和分子机理。具体而言，我们将研究SMCX是否在形成各种记忆的形成中起一般作用，包括短期和长期记忆。我们将研究与SMCX损失相关的记忆缺陷的细胞基础。具体而言，我们将确定SMCX的损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研究，以确定SMCX损失对长期增强和抑郁的影响。这些实验将提供有关SMCX调节记忆形成的细胞机制的新见解。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由SMCX调节的SMCX结合位点和基因表达网络来解决这个问题。基于我们的初步数据，将特别注意SMCX可能有助于通过其脱甲基酶活性产生H3K4ME1（具有不清功能性作用的定义组蛋白修饰）的增强剂，从而有助于在记忆形成过程中依赖活性依赖性神经元基因转录。研究结果不仅将提供有关SMCX如何调节认知的重要分子见解，而且还阐明了H3K4ME1在增强子处的功能作用，这在表观遗传领域仍然是一个重要的问题。综上所述，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，当出现问题时，会导致人类疾病（例如MR）。