Dynamics of the brain epigenome with aging

大脑表观基因组随衰老的动态

• 批准号: 9898315
• 负责人: WILLARD M FREEMAN
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898315
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Animal Model; Animals; Area; Astrocytes; Bioinformatics; Biological; Brain; Caloric Restriction; Cell surface; Cells; Chromatin; Climacteric; Clinical; Correlative Study; Cytosine; DNA; DNA Methylation; DNA Modification Process; Data; Data Set; Databases; Dementia; Development; Enhancers; Entropy; Epigenetic Process; Female; Functional disorder; Future; Gene Expression; Gene Expression Regulation; Genome; Genomic Segment; Genomics; Goals; Hippocampus (Brain); Human; Impaired cognition; Intervention; Intervention Studies; Knowledge; Location; Longevity; Metabolic dysfunction; Methods; Methylation; Microglia; Mitotic; Modification; Morbidity - disease rate; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Nucleic Acid Regulatory Sequences; Oklahoma; Pathway interactions; Pattern; Play; Population; Predisposition; Prevention; Process; Regulation; Reporting; Research; Resistance; Role; Sex Differences; Shock; Site; Site-Directed Mutagenesis; Study models; Techniques; Technology; Testing; Tissues; Veterans; age related; age related neurodegeneration; aged; aging brain; base; bisulfite sequencing; cell type; design; epigenome; epigenome editing; epigenomics; experience; genome sequencing; genome-wide; genomic locus; innovation; insight; male; middle age; mortality; nervous system disorder; novel; prevent; programs; response; sex; tool; transcription factor; transcriptome sequencing; whole genome

Regulation of brain aging through epigenetic processes is currently one of the most provocative areas of aging research. Epigenetic processes in the central nervous system may play a mechanistic role in susceptibility to and progression of cognitive decline and age-related neurodegenerative disease such as Alzheimer’s disease and other dementias. DNA modifications, principally methylation and hydroxymethylation of cytosines (mC and hmC respectively), are fundamental regulators of DNA accessibility and gene regulation/expression with differential effects on gene expression depending on the modification (mC/hmC), context CG/CH, and genomic location. A barrier to progress in understanding the role of epigenetic mechanisms in brain aging, and DNA modifications in particular, has been the lack of quantitatively accurate, genome-wide data. Without the knowledge of the specific genomic locations of altered modifications with aging and it is impossible to design well-rationalized, mechanistic studies that unravel the functional effects of epigenetic changes. Therefore, the critical next step for the field is to generate this genome-wide data of mC and hmC in CG and CH contexts in specific cell types and in both males and females. To address this barrier to progress we have developed innovative methods to analyze mC and hmC levels across the genome with absolute quantitation in a base- and strand-specific manner. Using these novel tools, we have found that there are significant changes with aging in the patterns of hippocampal mC and hmC, that these changes are principally sex-specific, and they correspond to altered gene expression. Intriguingly, we have also identified non-CpG methylation as the primary form of altered methylation with aging and a male-specific increased inter-animal variance (methylation entropy) across the genome with aging in the hippocampus. These findings raise significant questions that must be addressed to move the field to mechanistic studies. Is the neuroepigenome altered in a similar or dissimilar manner across CNS cell types and between sexes? Can age-related changes in the neuroepigenome be prevented? What regions of the genome should be targeted by epigenome editing approaches to test whether brain aging can be prevented or reversed by maintaining or restoring a ‘youthful’ DNA modification pattern? In Aim 1, cell type-specific changes in mC/hmC with aging in the CNS of male and female mice will be examined by whole genome sequencing (WGoxBS). Microglia, astrocytes, and neurons isolated from the hippocampus by both cell surface markers and NuTRAP technology will be examined. Young (3M), Adult (12M), and Aged (24M) C57Bl6 male and female mice will be examined and mC/hmC data will be concatenated with paired RNA-Seq data. Bioinformatic approaches will then be used to determine the role of altered modification patterns in age-related changes in gene expression, enrichment of differential modifications in regulatory regions of the genome, and to identify genomic loci for epigenome editing. In Aim 2 the ability of caloric restriction to prevent age-related changes in DNA methylation and hydroxymethylation and maintain a ‘young’ neuroepigenome will be determined in neurons, astrocytes, and microglia. At the tissue level, we have found prevention of age-related epigenomic changes by caloric restriction in males but the effects on isolated cell populations and females are unknown. Using a unique database of all publicly available, annotated human methylation data we will validate aspects of our finding in humans. These studies will allow the determination of critical genomic regions with altered DNA modification patterns that can be manipulated in future interventional studies. The ultimate goal of the research being clinical interventions that target the epigenome to maintain brain function with aging and prevent age-related neurological disease in Veterans.

通过表观遗传过程调节大脑衰老是当前衰老的最挑衅的领域之一 研究。中枢神经系统中的表观遗传过程可能在易感性方面发挥机械作用 认知能力下降和与年龄有关的神经退行性疾病的进展，例如阿尔茨海默氏病 和其他痴呆症。 DNA修饰，主要是胞嘧啶的甲基化和羟甲基（MC和 HMC分别是DNA可及性和基因调节/表达的基本调节剂 根据修饰（MC/HMC），上下文CG/CH和基因组的差异对基因表达的影响 地点。在理解表观遗传机制在大脑衰老和DNA中的作用方面进步的障碍 特别是修改是缺乏定量准确的全基因组数据。没有 了解改变修饰的特定基因组位置随着衰老而变化，并且无法设计 良好的理性机械研究，揭示了表观遗传变化的功能效应。因此， 该领域的关键下一步是在CG和CH上下文中生成MC和HMC的全基因组数据 特定的细胞类型以及男性和女性。为了解决这个进步的障碍，我们已经发展了 在基础上以绝对定量分析基因组MC和HMC水平的创新方法 和特定于链的方式。使用这些新颖的工具，我们发现 在海马MC和HMC的模式下，这些变化主要是性别特定的，它们 对应于改变基因表达。有趣的是，我们还确定了非CPG甲基化 随着衰老和男性特异性增加的甲基化改变甲基化的主要形式（甲基化） 熵）穿过基因组，在海马中衰老。这些发现提出了重大问题 必须解决将领域转移到机械研究中。在类似的或 CNS细胞类型以及性别之间的不同方式？可以与年龄有关的变化 防止神经兴奋剂组吗？表观基因组编辑应针对哪些基因组区域 通过维护或恢复“年轻”或恢复，测试是否可以预防或逆转大脑衰老的方法 DNA修饰模式？在AIM 1中，MC/HMC的细胞类型特异性变化，男性中枢神经系统的老化和 将通过整个基因组测序（WGOXB）检查雌性小鼠。小胶质细胞，星形胶质细胞和神经元 将检查由细胞表面标记和营养技术从海马分离出来的。年轻的 （3M），成人（12m）和年龄（24m）C57BL6雄性和雌性小鼠将进行检查，MC/HMC数据将为 与配对的RNA-seq数据串联。然后将使用生物信息学方法来确定 与年龄相关的基因表达变化变化的修饰模式改变，差异的富集 基因组调节区域的修饰，并确定表观基因组编辑的基因组位置。在目标2中 热量限制防止DNA甲基化和羟甲基化和 将在神经元，星形胶质细胞和小胶质细胞中确定保持“年轻”神经兴奋剂组。在组织 水平，我们发现预防男性热量限制与年龄相关的表观基因组学变化，但 对孤立的细胞群体和女性的影响尚不清楚。使用所有公开可用的唯一数据库 注释的人类甲基化数据我们将验证我们在人类中发现的各个方面。这些研究将允许 确定可以在 未来的介入研究。研究的最终目标是针对的临床干预措施 表观基因组可维持大脑功能，并预防退伍军人与年龄有关的神经系统疾病。