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: 10488179
• 负责人: Samuel Beck
• 金额: $ 47.02万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10488179
• 关键词: 3-Dimensional; Address; Age; Age of Onset; Aging; Architecture; Automobile Driving; Bromodomain; 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; Gene Silencing; 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; Pharmacology; 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; inhibitor; innovation; ischemic cardiomyopathy; mRNA sequencing; mouse model; novel; 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。核层的破坏和相关 异染色质通常在各种衰老环境中观察到，包括早衰病、细胞 衰老，和正常衰老。尽管这些共同的结构变化已经报道了两个多月 几十年来，它们对转录的影响以及对年龄相关退行性变化的贡献仍然存在 未知。通过计算分析，我们最近发现CpG岛(CGI)，哺乳动物 启动子相关元件，为回答这个问题提供了重要线索。在人类中，大约60%的 基因在其启动子(CGI+基因)处含有CGI，并在全身广泛表达，而 其他40%没有CGI(CGI基因)的基因表现出组织限制性表达模式。我们的 初步结果表明，在年轻的细胞核中，只有cgi基因可以驻留在与膜相关的膜内。 异染色质，当转录不活跃时。这表明，衰老介导的异染色质 解凝集和椎板破坏会特别阻碍CGI基因的抑制状态。我们的数据 确实表明超过30%的CGI基因在各种衰老组织中被错误激活，这一模式与此相吻合 器官功能的丧失。在这个项目中，我们将检验新的假设：1)染色质的变化 衰老过程中的结构直接触发CGI基因在组织/上下文中的不受控制的表达 不应该表达，这反过来又会加速与年龄相关的恶化。我们还将测试 3)对CGI基因错误表达的药理抑制延缓了与年龄相关的退行性改变。