The metabolic-epigenetic axis in memory

记忆中的代谢-表观遗传轴

基本信息

批准号：
9764788
负责人：
SHELLEY L BERGER
金额：
$ 44.73万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-15 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9764788
关键词：
Abstinence Acetate-CoA Ligase Acetates Acetyl Coenzyme A Alcohol abuse Alcoholic beverage heavy drinker Alcohols Attention Behavior Behavioral Binding Brain CRISPR/Cas technology Carbon Cell Nucleus Cells Chromatin Chromatin Loop Cytoplasm Data Deposition Disease Dorsal Enhancers Enzymes Epigenetic Process Ethanol Family member Future Gene Expression Generations Genes Genetic Genetic Transcription Genome Genomics Higher Order Chromatin Structure Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histones Human In Vitro Investigation Learning Link Mass Spectrum Analysis Mediating Memory Memory impairment Mental disorders Metabolic Metabolism Mitochondria Modeling Modification Molecular Mus Neurobiology Neuroglia Neurologic Neuronal Differentiation Neuronal Plasticity Neurons Nuclear Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Play Population Post-Translational Protein Processing Proteins Regulation Regulatory Element Regulatory Pathway Relapse Rodent Role Societies Substance Use Disorder Therapeutic Therapeutic Intervention Transcript Transcriptional Regulation Work addiction alcohol behavior alcohol exposure alcohol use disorder base chromatin modification chromatin remodeling classical conditioning cognitive process craving epigenetic regulation epigenome genome-wide histone acetyltransferase improved in vivo inhibitor/antagonist knock-down mouse model neuropsychiatry novel novel therapeutics object recognition preference promoter protein complex recruit response small hairpin RNA small molecule spatial memory targeted treatment therapeutic target tool transcriptome sequencing

Abstinence Acetate-CoA Ligase Acetates Acetyl Coenzyme A Alcohol abuse Alcoholic beverage heavy drinker Alcohols Attention Behavior Behavioral Binding Brain CRISPR/Cas technology Carbon Cell Nucleus Cells Chromatin Chromatin Loop Cytoplasm Data Deposition Disease Dorsal Enhancers Enzymes Epigenetic Process Ethanol Family member Future Gene Expression Generations Genes Genetic Genetic Transcription Genome Genomics Higher Order Chromatin Structure Hippocampus (Brain)Histone Acetylation Histone Deacetylase Histones Human In Vitro Investigation Learning Link Mass Spectrum Analysis Mediating Memory Memory impairment Mental disorders Metabolic Metabolism Mitochondria Modeling Modification Molecular Mus Neurobiology Neuroglia Neurologic Neuronal Differentiation Neuronal Plasticity Neurons Nuclear Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Play Population Post-Translational Protein Processing Proteins Regulation Regulatory Element Regulatory Pathway Relapse Rodent Role Societies Substance Use Disorder Therapeutic Therapeutic Intervention Transcript Transcriptional Regulation Work addiction alcohol behavior alcohol exposure alcohol use disorder base chromatin modification chromatin remodeling classical conditioning cognitive process craving epigenetic regulation epigenome genome-wide histone acetyltransferase improved in vivo inhibitor/antagonist knock-down mouse model neuropsychiatry novel novel therapeutics object recognition preference promoter protein complex recruit response small hairpin RNA small molecule spatial memory targeted treatment therapeutic target tool transcriptome sequencing

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项目摘要

Abstract Understanding the molecular machinery underlying learning is critical to improve therapies for memory-related disorders that continue to burden our society. We recently identified a connection between cellular metabolism, epigenetic regulation, and memory-related neuronal plasticity. We found that ACSS2, a metabolic enzyme that generates acetyl-CoA is chromatin-bound in hippocampal neurons and required for long-term spatial memory, a cognitive process that relies on histone acetylation and gene expression. While these results established a strong functional link between nuclear acetyl-CoA generation by ACSS2, histone acetylation, transcription and memory, the exact molecular underpinnings of this metabolic- epigenetic axis remain to be elucidated. Here we propose to explore this phenomenon in further mechanistic detail. In particular, we aim to identify ACSS2-associated proteins, examine the mechanism of ACSS2 recruitment to specific genes, and identify higher-order structures that contribute to ACSS2-mediated transcriptional regulation via chromatin looping. Moreover, we will explore dorsal hippocampal transcriptional and epigenetic changes that accompany memory formation in a hippocampus-dependent mammalian learning model (spatial object recognition). We will assess genome-wide changes in transcript abundance and chromatin accessibility, study the enrichment of histone post-translational modifications, and the re-distribution of ACSS2 and select histone acetyl marks. Finally, using an array of pharmacological and genetic tools, we will assess the contribution of ACSS2 to the observed transcriptional, epigenetic and behavioral phenotypes. In addition, our preliminary data under Aim 3 indicate that ethanol-derived acetyl-groups are rapidly incorporated into neuronal chromatin in an ACSS2-dependent manner. This remarkably rapid epigenetic response might underlie alcohol-induced transcriptional and behavioral maladaptations in heavy drinkers. Indeed, we found that treating primary hippocampal neurons with acetate (the alcohol-derived metabolite and direct substrate of ACSS2) upregulates learning and memory-related genes and that ACSS2 reduction eliminates alcohol-related associative learning in conditioned place preference. We will explore hippocampal transcriptional and epigenetic changes associated with alcohol exposure in mice in vivo and assess the contribution of ACSS2 to molecular and cellular alterations induced by alcohol. Further, we will assess the effect of small molecule ACSS2 inhibitors on alcohol-related behaviors, as a basis for future therapeutic interventions. Overall, this work will significantly advance the field by characterizing the metabolic-epigenetic axis in the context of learning neurobiology. Furthermore, we expect our studies to identify efficacious novel therapeutic avenues for memory impairments and associated neurological and psychiatric conditions.

抽象的了解基础学习的分子机械对于改善与内存有关的疗法至关重要继续负担我们社会的疾病。我们最近确定了细胞代谢之间的联系，表观遗传调节和与记忆相关的神经元可塑性。我们发现ACSS2是一种代谢酶生成乙酰辅酶A是海马神经元中染色质结合的，需要长期空间记忆，依赖组蛋白乙酰化和基因表达的认知过程。尽管这些结果建立了通过 ACSS2，组蛋白乙酰化，转录和记忆，该代谢的确切分子基础表观遗传轴仍有待阐明。在这里，我们建议在进一步的机械上探索这种现象细节。特别是，我们旨在鉴定与ACS2相关的蛋白质，检查ACSS2的机制招募特定基因，并确定有助于ACSS2介导的高阶结构通过染色质循环调节转录调节。此外，我们将探索背部的背部转录以及在海马依赖性哺乳动物学习中伴随记忆形成的表观遗传变化模型（空间对象识别）。我们将评估全基因组丰度的变化和染色质的可及性，研究组蛋白后翻译后修饰的富集以及重新分布 ACSS2和选择组蛋白乙酰基标记。最后，使用一系列药理和遗传工具，我们将评估ACSS2对观察到的转录，表观遗传和行为表型的贡献。此外，我们在目标3下的初步数据表明，乙醇衍生的乙酰基群迅速以ACSS2依赖性方式掺入神经元染色质。这种非常快速的表观遗传反应可能是饮酒引起的重量饮酒者的转录和行为不适的基础。确实，我们发现用乙酸乙酸盐治疗原发性海马神经元（酒精衍生的代谢产物和 ACSS2的直接底物2）上调学习和记忆相关的基因，并降低ACSS2 在条件地点偏好中消除与酒精相关的关联学习。我们将探索海马体内与小鼠酒精暴露有关的转录和表观遗传变化，并评估 ACS2对酒精诱导的分子和细胞改变的贡献。此外，我们将评估小分子ACSS2抑制剂对酒精相关行为的影响，作为将来治疗的基础干预措施。总体而言，这项工作将通过表征代谢性诊断轴来大大推动该领域学习神经生物学的背景。此外，我们希望我们的研究能够确定有效的小说用于记忆障碍以及相关神经和精神病的治疗途径。