Single-Cell Analysis of Aging-Associated 4D Nucleome in the Human Hippocampus

人类海马中与衰老相关的 4D 核组的单细胞分析

• 批准号: 10267725
• 负责人: Carl Wayne Cotman
• 金额: $ 60.7万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10267725
• 关键词: Affect; Age; Age-Months; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animals; Architecture; Area; Atlases; Autopsy; Biological Process; Brain; Brain region; Brain-Derived Neurotrophic Factor; Caring; Cells; Chromatin; Chromatin Structure; Cognitive; Complement; DNA; DNA Methylation; DNA methylation profiling; Data; Diet; Enhancers; Exercise; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genomics; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Individual; Intervention; Joints; Longevity; Maps; Measures; Medical; Methods; Molecular; Molecular Profiling; Monitor; Mus; Neurodegenerative Disorders; Nuclear; Pattern; Physical Exercise; Physical activity; Population; Process; Regulation; Regulator Genes; Research; Resolution; Role; Running; Sampling Studies; Smoking; Testing; Uncertainty; United States; Work; age group; age related; aging brain; base; brain cell; cell type; cognitive function; cohort; epigenome; exercise intervention; genomic data; human data; human subject; improved; interest; lifestyle factors; methylome; mind control; mouse model; multiple omics; neural circuit; neurotrophic factor; new therapeutic target; normal aging; novel; novel strategies; programs; promoter; response; sedentary; single cell analysis; tool; transcriptome

Project Summary / Abstract Age-related cognitive decline is an important concern in the United States, as approximately 20% of the US population is expected to be age 65 or older by year 2030. Understanding the molecular mechansims of brain aging to prolong healthy cognitive function is therefore increasingly important as the population ages and older people remain in the work force. Brain cells exhibit profound and heterogeneous changes during aging at molecular and cellular levels. The simple intervention of physical exercise has emerged as a major positive modulator of cognitive function in aging. In response to RFA-RM-20-005, we have formed an interdisciplinary team with expertise in single-cell genomics, neural circuitry, and aging, to investigate age- and physical activity- related changes of 4D nucleome in post-mortem human brain hippocampus cells across the lifespan with single- cell resolution. We hypothesize that cell-type-specific re-organization of nucleome occurs in the human hippocampal brain region during aging and with physical activity. The changes in nucleome in turn control brain epigenome and transcriptome, modulating neural circuit functionality. The “Methyl-HiC”, a new approach for joint profiling of DNA methylation and chromatin contacts in single cells, combined with “Paired-seq”, an ultra- high-throughput method for single-cell joint analysis of open chromatin and transcriptome, will be used to interrogate the chromatin architecture along with DNA methylation, chromatin accessibility and gene expression in the human hippocampus. In Aim 1, we will determine changes in nucleome in major cell types of post-mortem human hippocampus across the life-span with 4 age ranges (20–39, 40–59, 60–79, and 80–99 years old). We will further correlate these changes in nucleome with epigenome and transcriptome in each cell type, to identify vulnerable cell types during aging, and uncover potential gene regulatory programs that could be impacted by aging. In Aim 2, we will determine how physical activity modifies and restores nucleome in specific human hippocampal cell types. We will study two age-matched cognitively–healthy cohorts (70-99 years old) with either high level or low level physical activity, as measured by wearable activity monitors. We will correlate restorative effects on nucleome with epigenome and transcriptome. In Aim 3, we will map how aging and exercise alter nucleome in specific hippocampal cell types with highly controlled quantifiable physical activity in the mouse model, for comparison with human data. These mouse studies allow the exercise variable to be investigated in isolation from effects of other lifestyle factors that can affect hippocampal nucleome, which is not possible with human subjects. The proposed research will help to transform our ability to understand the mechanisms of chromatin organization and function in the context of human brain aging.

项目概要/摘要 在美国，与年龄相关的认知能力下降是一个重要问题，因为大约 20% 的人 到 2030 年，美国人口预计将达到 65 岁或以上。了解其分子机制 因此，随着人口老龄化和人口老龄化，通过大脑老化来延长健康的认知功能变得越来越重要。 老年人仍留在劳动力队伍中。脑细胞在衰老过程中表现出深刻且异质的变化 分子和细胞水平。体育锻炼的简单干预已成为一大积极因素 衰老过程中认知功能的调节剂。为了响应 RFA-RM-20-005，我们成立了一个跨学科的团队 拥有单细胞基因组学、神经回路和衰老方面的专业知识的团队，研究年龄和身体活动- 死后人脑海马细胞 4D 核组在整个生命周期中的相关变化 细胞分辨率。我们假设细胞类型特异性的核组重组发生在人类中 衰老和体力活动期间的海马大脑区域。核组的变化反过来控制大脑 表观基因组和转录组，调节神经回路功能。 “Mmethyl-HiC”，一种新方法 单细胞中 DNA 甲基化和染色质接触的联合分析，结合“Paired-seq”（一种超 用于开放染色质和转录组的单细胞联合分析的高通量方法，将用于 探究染色质结构以及 DNA 甲基化、染色质可及性和基因表达 在人类海马体中。在目标 1 中，我们将确定死后主要细胞类型的核组变化 人类整个生命周期的海马体有4个年龄范围（20-39岁、40-59岁、60-79岁和80-99岁）。我们 将进一步将每种细胞类型中核组的这些变化与表观基因组和转录组相关联，以确定 衰老过程中脆弱的细胞类型，并发现可能受到影响的潜在基因调控程序 老化。在目标 2 中，我们将确定体力活动如何改变和恢复特定人类的核组 海马细胞类型。我们将研究两个年龄匹配的认知健康群体（70-99 岁） 由可穿戴活动监测器测量的高水平或低水平身体活动。我们将把恢复性的 表观基因组和转录组对核组的影响。在目标 3 中，我们将绘制衰老和运动如何改变的图 小鼠特定海马细胞类型的核组，具有高度受控的可量化体力活动 模型，用于与人类数据进行比较。这些小鼠研究允许对运动变量进行研究 隔离可能影响海马核组的其他生活方式因素的影响，这是不可能的 人类受试者。拟议的研究将有助于转变我们理解机制的能力 人类大脑衰老背景下的染色质组织和功能。