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。核薄片和 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，细胞感应和正常衰老。提出了这些结构性变化，以触发 至少两个基因子集的转录消除：线1（L1）和缺乏CpG岛的基因（CGI- 基因）。 L1的转录增加，人类中唯一的主动逆转元件（RTE）， 其监视机制的失败导致胞质RTE cDNA通过逆转录形成 老年组织中的慢性无菌炎症。同时，我们已经表明异染色质反应 在老化的细胞中，导致CGI基因的不受控制的表达，这些表达通常与异染色质相关 正常条件（cgi基因的明显）。 CGI基因的异常激活驱动了各种年龄 相关的退行性变化，包括先前确定的衰老标志，范围从细胞损失 功能身份和增加转录噪声的增加，与年龄相关的秘书表型与慢性 炎。这些先前的观察提案，染色质体系结构混乱和结果 L1和Cgi Gene激活是多元衰老标志的主要煽动者。我们的初步 分析表明，这种关系不是单向的。 L1激活和CGI基因将 相互激活，此外，还促进了染色质结构的破坏。这项建议的研究 将检验新的假设，即RTE/CGI基因/核结构之间的相互激活形成A “恶性循环”在衰老过程中加剧了身体恶化。在AIM 1中，我们将验证相互的 正常老化期间染色质结构的破坏与RTE激活之间的激活效应。目标2 将检验以下假设，即与年龄相关的L1激活通过触发CGI-促进身体恶化 基因misexpression。在AIM 3中，我们将测试以下假设 染色质体系结构可以局部/系统地传播核结构的破坏和L1激活。