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.

项目概要 核/染色质结构的变化是核纤层和细胞核老化的标志。 相关的异染色质通常在各种衰老背景下观察到，包括过早衰老 疾病、细胞衰老和正常衰老被认为是引发这些结构变化的原因。 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- 基因）的转录增加，L1 是人类中唯一的活性逆转录转座元件（RTE）。 其监视机制的失败导致通过逆转录形成胞质 RTE cDNA，从而导致 同时，我们已经证明了衰老组织中的慢性无菌炎症。 衰老细胞中的 CGI 基因表达失控，通常与异染色质相关 正常情况下（CGI-基因的错误表达）。CGI-基因的异常激活驱动不同的年龄-。 相关的退行性变化，包括先前确定的衰老标志，包括细胞损失 功能同一性和转录噪音增加、年龄相关的分泌表型对慢性病的影响 这些先前的观察表明染色质结构紊乱以及由此产生的炎症。 L1 和 CGI​​ 基因激活是多种衰老特征的主要煽动者。 分析表明这种关系不是单向的；L1 激活和 CGI​​ 基因错误表达可能会导致这种关系。 相互激活，此外，促进染色质结构破坏。 将测试 RTE/CGI 基因/核结构之间的相互激活形成的新假设 衰老过程中生理恶化的“恶性循环”在目标1中，我们将验证相互之间的关系。 正常衰老过程中染色质结构破坏和 RTE 激活之间的激活效应。 将检验以下假设：与年龄相关的 L1 激活通过触发 CGI- 促进生理退化 在目标 3 中，我们将检验衰老细胞的分泌蛋白组被破坏的假设。 染色质结构可以局部/系统地传播核结构破坏和 L1 激活。