New roles for REST during brain maturation

休息在大脑成熟过程中的新作用

• 批准号: 10164872
• 负责人: Gail Mandel
• 金额: $ 52.15万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164872
• 关键词: Activator Appliances; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Behavioral; Binding; Binding Sites; Biological Models; Biology; Birth; Brain; Cell Line; Cell Nucleus; Cells; Centenarian; Chromatin; Chromatin Remodeling Factor; Complex; Cytoplasmic Granules; Development; Disease; Embryo; Event; Excision; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Grant; Heterogeneity; Hippocampus (Brain); Human; Human Genome; Impaired cognition; Individual; Knowledge; Laboratories; Life; Longevity; Mediating; Mitotic; Modeling; Mus; Neuronal Differentiation; Neurons; Nucleic Acid Regulatory Sequences; Orphan; Pathology; Phenotype; Play; Population; Proteins; Publishing; RE1-silencing transcription factor; RNA; RNA analysis; Regulation; Reporting; Role; Signal Transduction; Site; Testing; Time; Tissues; Transcription Repressor; age related; aging brain; cell type; chromatin modification; cofactor; cognitive function; emerging adult; epigenetic regulation; experimental study; genome integrity; interest; mouse development; mouse genome; postnatal; recruit; relating to nervous system; stem; stem cells; synaptogenesis; transcription factor REST

Despite advances in model systems for identifying genes involved in aging, many unanswered questions still remain about the biology and underlying mechanisms in humans, particularly related to age-related cognitive decline. This is, in part, because even between mouse and human genomes, genetic regulatory elements have diverged, in sequence, numbers, and their presence in different genes. Additionally, the extreme heterogeneity of cell types in brain is a factor. In this grant, we take on the challenging problem of genetic mechanisms underlying human brain aging. First, we exploit the accumulated wealth of knowledge of the transcriptional repressor, REST, to fully characterize its function in neurons in adult brain. We, and others, have been studying REST for decades as a model for understanding fundamentals of gene regulation because of some prominent features. REST has an easily recognizable unusually large binding site that occurs in thousands of neuronal genes and it robustly signals its function when bound to genes by recruiting chromatin modifiers. While others have reported an activator function for REST in neurons, we have only found repressor function, so we will also settle this discussion in Aim 1. Aim 1 also includes studies to identify “orphan” REST binding sites of unknown function. The results from this aim will expand the neuronal functions under REST control, as well as provide a potentially new model of repressor function, generally. Second, our preliminary results indicate REST is expressed to different levels in different neuronal types, human and mouse, and that its loss in mice results in differential transcriptional effects in these neurons. This parsing of REST function in human neurons is studied in depth in Aims 2 and 3. We recently found that REST protein levels in human hippocampus increase with age sometime in the second decade after birth, remaining elevated even in centenarians, whereas REST levels in mouse brain are greatly reduced by 4-6m after birth, and stay extremely low for life, suggesting human-specific REST functions and/or target genes with age. We will identify REST functions with age in Aim 2. Third, polymorphisms in REST have been associated with the age-related disease, Alzheimer's Disease (AD). A recent study suggests that REST is involved directly in cognitive decline, although some of the published findings are at odds with our results. We will test hypotheses regarding REST gene regulation in AD in Aim 3. In total, our proposed experiments will provide new information on REST function and its potential impact on neuronal gene expression and chromatin changes during brain aging and related pathologies. The experiments will also provide new information on fundamental questions regarding repressor function.

尽管模型系统的进步用于识别涉及衰老的基因，但许多未解决的问题 仍然存在有关人类的生物学和潜在机制，特别是与年龄有关 认知能力下降。这部分是因为即使在小鼠和人类基因组之间，遗传调节 元素在序列上差异及其在不同基因中的存在。另外， 大脑中细胞类型的极端异质性是一个因素。在这笔赠款中，我们处理了 人脑衰老的遗传机制。首先，我们利用了积累的财富 记录复制品的知识，休息，以充分表征其在成人中神经元中的功能 脑。我们和其他人一直在学习休息数十年，作为了解基本面的模型 由于某些突出特征，基因调节。休息很容易识别出异常大的 发生在数千个神经元基因中的结合位点，并在与 通过募集染色质修饰剂的基因。而其他人则报告了一个激活器功能，以便在 神经元，我们只找到了复制器功能，因此我们还将在AIM 1中解决此讨论。AIM 1也 包括研究未知功能的“孤儿”休息结合位点的研究。这个目标的结果将 扩展在休息控制下的神经元功能，并提供一个潜在的新模型 通常，阻遏函数。其次，我们的初步结果表明休息表达为不同 不同神经元类型的人类和小鼠的水平，并且它在小鼠中的损失导致差异 这些神经元中的转录作用。在人类神经元中进行的REST功能的解析是研究的 目标2和3中的深度。我们最近发现，人海马中的休息蛋白水平随着 出生后第二个十年的某个年龄，即使在一半的人中也保持着升高，而休息 出生后，小鼠大脑的水平大大降低了4-6m，并保持生命极低，表明 随着年龄的增长，人类特异性的休息功能和/或靶基因。我们将随着年龄的年龄确定休息功能 目标2。第三，休息中的多态性与年龄有关的疾病，阿尔茨海默氏病有关 疾病（AD）。最近的一项研究表明，休息直接参与认知能力下降，尽管有些人 已发表的发现与我们的结果不符。我们将测试有关REST基因的假设 AIM 3中的AD中的法规。总共，我们提出的实验将提供有关REST的新信息 功能及其对脑衰老过程中神经元基因表达和染色质变化的潜在影响 和相关的病理。实验还将提供有关基本问题的新信息 相关的代表性功能。

项目成果

The Genome-Wide Binding Profile for Human RE1 Silencing Transcription Factor Unveils a Unique Genetic Circuitry in Hippocampus.

人类 RE1 沉默转录因子的全基因组结合谱揭示了海马中独特的遗传电路。

• DOI: 10.1523/jneurosci.2059-20.2021
• 发表时间: 2021
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: McGann,JamesC;Spinner,MichaelA;Garg,SaurabhK;Mullendorff,KarinA;Woltjer,RandallL;Mandel,Gail
• 通讯作者: Mandel,Gail