Loss of transcriptional homeostasis of genes lacking CpG islands during aging

衰老过程中缺乏 CpG 岛的基因转录稳态丧失

• 批准号: 10814562
• 负责人: Samuel Beck
• 金额: $ 47.06万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10814562
• 关键词: 3-Dimensional; Acceleration; Address; Age; Age of Onset; Aging; Architecture; Automobile Driving; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Caenorhabditis elegans; Cardiomyopathies; Cell Aging; Cell Nucleus; Cells; Chromatin; Chronic; Computer Analysis; CpG Islands; Data; Deterioration; Development; Disease; Echocardiography; Elements; Exhibits; Functional disorder; Gene Expression; Genes; Genetic Transcription; Heart; Heterochromatin; Histology; Homeostasis; Human; Immune; Immunofluorescence Immunologic; Inflammation; Inflammatory; Longevity; Mediating; Mus; Noise; Nuclear; Nuclear Lamina; Oncogene Deregulation; Organ; Pathology; Pattern; Physiological; Plasma; Premature aging syndrome; Protein Family; Proteome; Pulmonary Fibrosis; RNA; Reporting; Research; Stroke; System; Testing; Time; Tissues; age related; aged; cytokine; drug repurposing; frailty; in silico; indexing; innovation; ischemic cardiomyopathy; mRNA sequencing; mouse model; novel; pharmacologic; promoter; single-cell RNA sequencing; systemic inflammatory response; therapeutically effective

PROJECT SUMMARY/ABSTRACT Changes in chromatin architecture is a hallmark of aging. Disruption of the nuclear lamina and associated heterochromatin are commonly observed in various aging contexts, including premature aging diseases, cellular senescence, and normative aging. Although these shared structural changes have been reported for over two decades, their impact on transcription and the contribution to age-related degenerative changes remains unknown. Through computational analysis, we recently identified that CpG islands (CGIs), mammalian promoter-associated elements, provide important clues to answering this question. In humans, about 60% of genes contain CGIs at their promoters (CGI+ genes) and are broadly expressed throughout the body, while the other 40% of genes that do not have CGIs (CGI- genes) exhibit tissue-restricted expression patterns. Our preliminary results demonstrate that, in young nuclei, only CGI- genes can reside within lamina-associated heterochromatin, when transcriptionally inactive. This suggests that aging-mediated heterochromatin decondensation and lamina disruption would specifically hinder the repressive status of CGI- genes. Our data indeed show over 30% of CGI- genes are mis-activated within various aged tissues, and this pattern coincides with the loss of organ function. In this project, we will test the novel hypothesis that 1) changes in chromatin architecture during aging directly trigger uncontrolled expression of CGI- genes in tissues/contexts where they should not be expressed and this, in turn, 2) accelerates age-associated deterioration. We will also test whether the 3) pharmacological inhibition of CGI- gene misexpression delay age-related degenerative changes.

项目摘要/摘要 染色质结构的变化是衰老的标志。核薄片和相关的破坏 在各种衰老的情况下通常观察到异染色质，包括过早衰老疾病，细胞 衰老和规范性衰老。尽管已报告了这些共享的结构变化超过两个 几十年来，它们对转录的影响以及对年龄相关的退行性变化的贡献仍然存在 未知。通过计算分析，我们最近确定了CPG岛（CGIS），哺乳动物 与启动子相关的元素，为回答这个问题提供了重要的线索。在人类中，约有60％ 基因在其启动子（CGI+基因）中包含CGI，并且在整个体内广泛表达 其他40％没有CGI（CGI基因）的基因表现出组织限制的表达模式。我们的 初步结果表明，在年轻的核中，只能属于层层相关的基因 转录无活性时异染色质。这表明衰老介导的异染色质 降解和椎板破坏会特别阻止cgi基因的抑制作用。我们的数据 实际上，超过30％的CGI基因在各种老年组织中被误激活，并且这种模式重合 随着器官功能的丧失。在这个项目中，我们将测试新的假设，即1）染色质的变化 衰老过程中的结构直接触发了在组织/环境中的cgi基因的不受控制的表达 不应表达，这反过来2）加速与年龄相关的恶化。我们还将测试是否 3）药理学抑制CGI基因延迟延迟与年龄相关的退行性变化。