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.

项目总结/文摘