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.

项目总结 核/染色质结构的变化是衰老的标志。核层的破坏和 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。这些结构性变化的提出是为了触发 至少两个基因亚集的转录下调：LINE-1(L1)和缺少CpG岛的基因(CGI- 基因)。增加L1的转录，L1是人类唯一活跃的逆转座子(RTES)，以及 其监控机制的失败导致胞浆RTE cDNAi通过逆转录形成，从而导致 老年组织中的慢性无菌炎症。同时，我们已经证明了异染色质解缩 导致CGI基因的不受控制的表达，通常与老年细胞中的异染色质有关 正常情况(CGI基因的错误表达)。CGI基因的异常激活驱动着不同年龄的- 相关的退行性变化，包括先前确立的衰老特征，从细胞丢失 功能认同和转录噪音增加，与年龄相关的分泌表型转变为慢性 发炎。这些先前的观察表明，染色质结构的解体和由此产生的 L1和CGI基因激活是衰老的多变量特征的主要始作俑者。我们的预赛 分析表明，这种关系不是单向的；L1激活和CGI基因错误表达将 相互激活，并进一步促进染色质结构的破坏。这项拟议的研究 将检验这一新的假设，即RTE/CGI基因/核结构之间的相互激活形成 “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 在正常老化过程中，染色质结构破坏和RTE激活之间的激活效应。目标2 将测试与年龄相关的L1激活通过触发CGI促进生理恶化的假设 基因错误表达。在目标3中，我们将检验这样一种假设，即老化细胞的分泌体被破坏 染色质结构可以局部/系统地传播核结构破坏和L1激活。