Dynamics of the brain epigenome with aging

大脑表观基因组随衰老的动态

基本信息

  • 批准号:
    10158418
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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目前衰老最具挑衅性的领域之一 research.中枢神经系统中的表观遗传过程可能在易感性中起机械作用。 以及认知能力下降和年龄相关的神经退行性疾病如阿尔茨海默病的进展 和其他痴呆症。DNA修饰,主要是胞嘧啶的甲基化和羟甲基化(mC和 hmC),是DNA可及性和基因调控/表达的基本调节因子, 根据修饰(mC/hmC)、背景CG/CH和基因组对基因表达的不同影响 位置.阻碍理解表观遗传机制在脑老化中的作用, 特别是基因组修饰,一直缺乏定量准确的全基因组数据。未经 随着年龄的增长,改变修饰的特定基因组位置的知识,并且不可能设计 合理化的机制研究,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背景下生成mC和hmC的全基因组数据, 特定的细胞类型和男性和女性。为了解决这一障碍,我们制定了 创新的方法来分析整个基因组的mC和hmC水平,并在基础上进行绝对定量, 和链特异性方式。使用这些新工具,我们发现, 海马mC和hmC模式的老化,这些变化主要是性别特异性的, 与基因表达的改变相对应。有趣的是,我们还确定了非CpG甲基化是 主要形式的甲基化改变与老化和雄性特异性增加动物间的差异(甲基化 熵)在基因组中与海马体中的衰老有关。这些发现提出了重要的问题, 必须解决这个问题,以推动该领域的机械研究。神经表观基因组是否在类似或 不同的方式在中枢神经系统细胞类型和性别之间?与年龄有关的变化 神经表观基因组可以预防吗?表观基因组编辑应该针对基因组的哪些区域 测试大脑衰老是否可以通过维持或恢复“年轻”来预防或逆转的方法 DNA修改模式?在目的1中,在雄性和雌性大鼠的CNS中,mC/hmC的细胞类型特异性变化随着年龄的增长而增加。 通过全基因组测序(WGoxBS)检查雌性小鼠。小胶质细胞、星形胶质细胞和神经元 将检查通过细胞表面标记和NuTRAP技术从海马分离的细胞。年轻 (3M)将检查成年(12 M)和老年(24 M)C57 B16雄性和雌性小鼠,并将计算mC/hmC数据。 与配对的RNA-Seq数据连接。生物信息学方法将用于确定 基因表达中与年龄相关的改变的修饰模式, 本发明的目的是提供用于在基因组的调控区中进行修饰的方法,以及鉴定用于表观基因组编辑的基因组基因座。在目标2中 热量限制预防与年龄相关的DNA甲基化和羟甲基化变化的能力, 维持“年轻”的神经表观基因组将在神经元、星形胶质细胞和小胶质细胞中确定。在组织 水平,我们已经发现男性通过限制热量来预防与年龄相关的表观基因组变化, 对分离的细胞群和雌性的影响尚不清楚。利用一个独特的数据库, 注释的人类甲基化数据,我们将验证我们在人类中发现的方面。这些研究将使 确定具有改变的DNA修饰模式的关键基因组区域, 未来的干预性研究。这项研究的最终目标是临床干预, 表观基因组,以维持大脑功能与衰老和预防与年龄有关的神经系统疾病的退伍军人。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cell-Specific Paired Interrogation of the Mouse Ovarian Epigenome and Transcriptome.
  • DOI:
    10.3791/64765
  • 发表时间:
    2023-02-24
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Ocañas SR;Isola JVV;Saccon TD;Pham KD;Chucair-Elliott AJ;Schneider A;Freeman WM;Stout MB
  • 通讯作者:
    Stout MB
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WILLARD M FREEMAN其他文献

WILLARD M FREEMAN的其他文献

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{{ truncateString('WILLARD M FREEMAN', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10594024
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Sex divergence and cell specificity of age-related hippocampal DNA modifications
年龄相关海马 DNA 修饰的性别差异和细胞特异性
  • 批准号:
    9766020
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
MOLECULAR ANALYSIS CELLULAR IMAGING (MACI) CORE
分子分析细胞成像 (MACI) 核心
  • 批准号:
    10536646
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
MOLECULAR ANALYSIS CELLULAR IMAGING (MACI) CORE
分子分析细胞成像 (MACI) 核心
  • 批准号:
    10320857
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
ShEEP Request for Laser Microdissection Instrument
ShEEP 请求激光显微切割仪器
  • 批准号:
    9796446
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Sex divergence and cell specificity of age-related hippocampal DNA modifications
年龄相关海马 DNA 修饰的性别差异和细胞特异性
  • 批准号:
    10063357
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Sex divergence and cell specificity of age-related hippocampal DNA modifications
年龄相关海马 DNA 修饰的性别差异和细胞特异性
  • 批准号:
    10385743
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Sex divergence and cell specificity of age-related hippocampal DNA modifications
年龄相关海马 DNA 修饰的性别差异和细胞特异性
  • 批准号:
    10615662
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Does Dietary Restriction Alter Stem Cell Function Through An Epigenetic Mechanism?
饮食限制是否通过表观遗传机制改变干细胞功能?
  • 批准号:
    9920075
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
MOLECULAR ANALYSIS CELLULAR IMAGING (MACI) CORE
分子分析细胞成像 (MACI) 核心
  • 批准号:
    10077912
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:

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