UNDERSTANDING CELLULAR AND TRANSCRIPTIONAL REGULATORY CHANGES IN HUMAN AGING

了解人类衰老过程中的细胞和转录调控变化

• 批准号: 10407046
• 负责人: John Greally
• 金额: $ 71.28万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407046
• 关键词: Adrenal Cortex Hormones; Affect; Age; Aging; Benchmarking; Binding; Binding Sites; Biological Assay; Biological Markers; Biology of Aging; CD4 Positive T Lymphocytes; Cell Lineage; Cell physiology; Cells; Characteristics; Chronic; Clonality; Cohort Studies; CpG dinucleotide; DNA Methylation; DNA Sequence; Data; Disease; Epigenetic Process; Event; Gene Expression; Generations; Genetic Polymorphism; Genetic Transcription; Genomics; Genotype; Glucocorticoid Receptor; Glucocorticoids; Goals; Human; Human Genome; In Vitro; Individual; Institution; Lead; Mediating; Memory; Modeling; Molecular; Outcome; Phenotype; Population; Process; Property; Publishing; Recommendation; Reporting; Research Design; Resistance; Role; Shock; Signal Transduction; Source; Stimulus; Stress; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; Tissues; Transcriptional Regulation; Variant; age related; base; cell type; cohort; design; epigenome-wide association studies; genome wide methylation; genome-wide; glucocorticoid-induced orphan receptor; human model; in vivo; innovation; insight; interest; memory CD4 T lymphocyte; novel; peripheral blood; response; transcription factor

The process of aging is believed to involve progressive loss of control of transcriptional regulation, in particular involving regulatory mechanisms referred to as “epigenetic”. These changes have been mostly characterized as an increase in variability of DNA methylation with age, referred to as epigenetic drift, with a subset of loci showing an intriguing, progressive change of DNA methylation that appears to act as an “epigenetic clock”. We note, however, that a DNA methylation assay reports much more than the transcriptional regulatory state of the cells studied. DNA methylation differences between individuals are now appreciated to indicate, for example, cell subtype compositional or DNA sequence differences, without any cells necessarily having changed their transcriptional regulation. DNA methylation is thus both a readout of transcriptional regulation and of other molecular and cellular processes, all generating changes in DNA methylation of the same modest magnitude. To perform a study that allows DNA methylation changes to be interpreted with confidence, we need to understand the sources of variability affecting this transcriptional regulator. A rigorous study should therefore include test genotypes, cell subtype proportions, and transcriptional variability, all of which can change DNA methylation values in a cell population. Furthermore, understanding the cis-regulatory landscape in the cells tested is essential, as this allows a focused analysis at loci informative for DNA methylation changes. An ideal cell type to use in an aging study is CD4+ T lymphocytes. Not only is this a cell type that appears to mediate a number of age-related phenotypes, and is accessible from peripheral blood for genome-wide assays of cohorts, it can also be tested for repertoire diversity using T cell receptor assays, and for cell subtype composition using multiple orthogonal techniques. We will use the strengths of our institution’s Nathan Shock Center of Excellence in the Biology of Aging to collect a well-phenotyped cohort for this study. Our data will reveal whether age-associated epigenetic changes occur independently of confounding influences, but will also allow us to uncover the other cellular and molecular events taking place in CD4+ T cells. An innovative goal is the identification of age-labile functional sequence variants, loci that change their ability to influence gene expression with age, a unique insight into the relationship between DNA sequence polymorphism and aging. We will also test the hypothesis that epigenetic clock CpGs represent loci mediating age-associated glucocorticoid receptor resistance, a separate model for age-associated compromise in cellular function. The outcome of this project will be the most rigorous and definitive study to date of epigenetic changes in aging. We expect human aging to involve a combination of cellular and molecular events. These findings will allow new, comprehensive insights into how CD4+ T cells are involved in mediating age-related diseases.

人们认为衰老过程涉及转录调控的逐渐丧失，特别是 这些变化的特点主要是 随着年龄的增长，DNA 甲基化的变异性增加，称为表观遗传漂变，其中有一部分位点 显示了 DNA 甲基化的有趣的渐进变化，它似乎充当了“表观遗传时钟”。 然而，我们注意到 DNA 甲基化检测报告的不仅仅是转录调控状态 所研究的细胞之间的 DNA 甲基化差异现在被认为可以表明，因为 例如，细胞亚型组成或 DNA 序列差异，但任何细胞不一定具有 DNA 甲基化改变了它们的转录调控。 以及其他分子和细胞过程，都会产生相同程度的 DNA 甲基化变化 震级。 为了进行一项能够自信地解释 DNA 甲基化变化的研究，我们需要 因此，应该进行严格的研究来了解影响这种转录调节因子的变异来源。 包括测试基因型、细胞亚型比例和转录变异性，所有这些都可以改变 DNA 此外，了解细胞中的顺式调控景观。 测试是必不可少的，因为这可以对提供 DNA 甲基化变化信息的位点进行集中分析。 用于衰老研究的理想细胞类型是 CD4+ T 淋巴细胞，这不仅是一种细胞类型。 介导许多与年龄相关的表型，并且可以从外周血中进行全基因组测定 队列中，还可以使用 T 细胞受体测定来测试库多样性，以及细胞亚型 我们将利用我们机构 Nathan Shock 的优势。 衰老生物学卓越中心为这项研究收集了一个表型良好的队列。 我们的数据将揭示与年龄相关的表观遗传变化是否独立于混杂因素发生 影响，但也将使我们能够发现 CD4+ T 中发生的其他细胞和分子事件 一个创新的目标是鉴定年龄不稳定的功能序列变异，即改变其细胞的基因座。 能够随年龄影响基因表达，对 DNA 序列之间关系的独特见解 我们还将检验表观遗传时钟 CpG 代表位点介导的假设。 年龄相关的糖皮质激素受体抵抗，是与年龄相关的细胞损害的一个单独模型 功能。 该项目的结果将是迄今为止关于表观遗传变化的最严格和最明确的研究 我们预计人类衰老涉及细胞和分子事件的结合。 允许对 CD4+ T 细胞如何参与介导与年龄相关的疾病提供新的、全面的见解。