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: 10667773
• 负责人: John Greally
• 金额: $ 8.64万
• 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/10667773
• 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，衰老的过程涉及转录调节的逐渐丧失，尤其是 涉及被称为“表观遗传学”的调节机制。这些变化主要是特征的 作为随着年龄的DNA甲基化变异性的增加，称为表观遗传漂移，其中一部分位点 显示出似乎充当“表观遗传时钟”的DNA甲基化的有趣，渐进的变化。 但是，我们注意到，DNA甲基化测定的报告远远超过转录调节状态 现在，对个体之间的DNA甲基化差异表示，以表明，因为 例如，细胞亚型组成或DNA序列差异，没有任何细胞必须具有 改变了他们的转录调节。因此，DNA甲基化既是转录调节的读数 以及其他分子和细胞过程的 震级。 要进行允许DNA甲基化变化以置信度解释的研究，我们需要 了解影响此转录调节器的可变性来源。因此，严格的研究应 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 细胞种群中的甲基化值。此外，了解细胞中的顺式调节景观 测试是必不可少的，因为这允许对DNA甲基化变化的局部信息进行重点分析。 在衰老研究中使用的理想细胞类型是CD4+ T淋巴细胞。这不仅是一种单元格类型 调解许多与年龄相关的表型，并可以从全基因组测定法的外围血液中获得 在队列中，还可以使用T细胞受体分析和细胞亚型测试它的曲目多样性 使用多种正交技术的组成。我们将利用机构内森震动的优势 衰老生物学的卓越中心，以收集良好的型号为这项研究。 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淆发生 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 细胞。一个创新的目标是识别年龄效率的功能序列变体，而改变了它们的基因座 能够随着年龄而影响基因表达，对DNA序列之间关系的独特见解 多态性和衰老。我们还将测试表观遗传时钟CPG代表局部介导的假设 与年龄相关的糖皮质激素受体抗性，这是一个单独的模型，用于在细胞中与年龄相关的折衷 功能。 该项目的结果将是迄今为止表观遗传变化的最严格，最明确的研究 老化。我们期望人衰老涉及细胞和分子事件的结合。这些发现会 允许对CD4+ T细胞如何参与介导与年龄有关的疾病的新综合见解。