Chromatin architecture disruption and the vicious cycle of aging.

染色质结构破坏和衰老的恶性循环。

• 批准号: 10901040
• 负责人: Samuel Beck
• 金额: $ 41.25万
• 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: 2023-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10901040
• 关键词: Address; Advanced Development; Adverse effects; Age; Aging; Architecture; Cell Aging; Cell Proliferation; Cells; Chromatin; Chronic; Complementary DNA; Computer Analysis; CpG Islands; DNA; Deterioration; Disease; Distal; Elements; Endocrine; Exposure to; Failure; Gene Activation; Genes; Genetic Transcription; Health; Heterochromatin; Human; In Vitro; Inflammation; Inflammatory; Link; Mediating; Mus; Noise; Nuclear; Nuclear Lamina; Outcome; Phenotype; Physiological; Play; Premature aging syndrome; Production; Progeria; Reverse Transcription; Signal Transduction; Sterility; Testing; Therapeutic; Tissues; Transcriptional Activation; Up-Regulation; age effect; aged; cell age; derepression; experimental study; functional loss; in vivo; innovation; mouse model; novel; paracrine; physiologic model; response; senescence; therapeutic target

PROJECT SUMMARY Changes in nuclear/chromatin architecture are 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. These structural changes were proposed to trigger the transcriptional derepression of at least two subsets of genes: LINE-1 (L1) and genes lacking CpG islands (CGI- genes). Increased transcription of L1, the only active retrotransposable elements (RTEs) in humans, and the failure of its surveillance mechanism result in cytosolic RTE cDNA formation via reverse transcription that causes chronic sterile inflammation in aged tissues. In parallel, we have shown that heterochromatin decondensation in aged cells causes uncontrolled expression of CGI- genes, which generally associate with heterochromatin in normal conditions (misexpression of CGI- genes). Aberrant activation of CGI- genes drives various age- associated degenerative changes, including previously established hallmarks of aging, ranging from cellular loss of functional identity and increased transcriptional noise, age-associated secretory phenotypes to chronic inflammation. These prior observations propose that chromatin architecture disorganization and the resulting L1 and CGI- gene activation play as a master instigator of multivariate hallmarks of aging. Our preliminary analysis suggests that this relationship is not unidirectional; L1 activation and CGI- gene misexpression would mutually activate each other and, furthermore, facilitate chromatin architecture disruption. This proposed study will test the novel hypothesis that the mutual activations among RTE/CGI- genes/nuclear architecture form a “vicious cycle” intensifying physiological deterioration during aging. In Aim 1, We will validate the mutual activation effects between chromatin architecture disruption and RTE activation during normative aging. Aim 2 will test the hypothesis that age-associated L1 activation facilitates physiological deterioration by triggering CGI- gene misexpression. In Aim 3, we will test the hypothesis that the secretome of aged cells with disrupted chromatin architectures can locally/systemically propagate nuclear architecture disruption and L1 activation.

项目摘要 核/染色质结构的变化是衰老的标志。核板层破坏， 相关的异染色质通常在各种衰老环境中观察到，包括过早衰老 疾病、细胞衰老和正常衰老。提出这些结构性变化是为了启动 至少两个基因子集的转录去抑制：LINE-1（L1）和缺乏CpG岛的基因（CGI-I）。 基因）。L1转录增加，人类唯一的活性逆转录转座因子（RTEs）， 其监视机制的失败导致通过逆转录形成胞质RTE cDNA， 老化组织的慢性无菌炎症。与此同时，我们已经表明，异染色质去凝聚， 在老化细胞中引起CGI基因的不受控制的表达，CGI基因通常与细胞中的异染色质有关， 正常条件（CGI基因的错误表达）。CGI基因的异常激活导致了不同的年龄- 相关的退行性变化，包括先前确定的衰老标志，从细胞丢失 功能的一致性和增加的转录噪音，年龄相关的分泌表型慢性 炎症这些先前的观察结果表明，染色质结构紊乱和由此产生的 L1和CGI-基因激活作为一个主煽动者的多变量老化的标志。我们的初步 分析表明，这种关系不是单向的，L1激活和CGI-基因的错误表达， 相互激活彼此，并且进一步促进染色质结构破坏。这项拟议的研究 将测试新的假设，即RTE/CGI-基因/核结构之间的相互激活形成了一个新的机制。 "恶性循环"加剧了衰老过程中的生理恶化。在目标1中，我们将验证相互 正常老化过程中染色质结构破坏和RTE激活之间的激活效应。目的2 将测试这一假设，即年龄相关的L1激活通过触发CGI促进生理恶化- 基因错误表达在目的3中，我们将检验衰老细胞的分泌组被破坏的假设。 染色质结构可以局部/系统地传播核结构破坏和L1激活。