Project 2: Chromatin, eigenome, and nuclear fidelity in senescence and aging

对动物模型的研究表明，遗传差异和体细胞突变是长寿的基础，但 非遗传因素也发挥了重要作用。大量的观察，包括我们的观察，表明 随着真核生物年龄的增长，表观遗传变化也会发生。然而，关键问题仍然存在，特别是，什么是 细胞衰老表型背后的驱动机制和基因组变化 还有衰老呢？我们的假设是，健康的衰老涉及表观基因组格局的动态平衡，我们 称为发色抑制，这种发色抑制在衰老过程中失效，导致组织退化和 自然死亡。因此，遗传方法和药物疗法来增强染色稳定性是一种 此P01应用程序和此项目2的所有协作项目的突出功能。 在之前的资金支持期间，我们展示了酵母染色质改变的关键功能。 哺乳动物衰老中的复制衰老和大量染色质改变。在下一个资助期，我们 将探索和阐明新的染色质调节途径，改变基因组功能在衰老和 衰老，导致色素不稳定的丧失。在初步研究中，我们新发现了染色质调节剂，其 还原延长了复制寿命，导致了维持表观基因组和转录组的新途径 在衰老过程中保持忠诚。我们还发现，LADS/染色质的核破坏和脱落到 衰老和衰老过程中的细胞质是通过典型的细胞质DNA传感途径感知的， CGAS-STING，进而触发细胞免疫途径和SASP(与衰老相关的 分泌表型)在衰老过程中最终导致组织损伤。 为了揭示这些新的染色质调节剂的机制和生理重要性 在衰老途径方面，我们将实现以下目标：1.研究基因内部的隐蔽转录 老化过程中的启动。我们假设基因内部转录激活位点会破坏正常启动。 并导致全球转录保真度的丧失，从而导致 染色质稳定。(2)研究与衰老相关的组蛋白乙酰化上调产生新的增强剂。我们 假设在衰老过程中，染色质稳定失调许可了新的增强剂，导致 反长寿基因的转录。(3)研究老化触发过程中染色质完整性的丧失 长寿染色质调节剂的炎症和自噬。我们的初步调查结果显示 细胞质中的LADS/染色质通过cGAS-STING触发促进衰老的细胞免疫途径。在 建议的研究，我们将揭开cGAS-STING在细胞内促进SASP计划的途径 衰老和与自然衰老相关的慢性炎症。 这项研究将产生改变寿命的新的表观遗传机制，并具有新的治疗方法的潜力。 旨在干预与年龄有关的疾病和延长健康寿命的目标。

Studies in animal models reveal that genetic differences and somatic mutations underlie longevity, but that non-genetic contributions also play a major role. Numerous observations, including our observations, suggest that epigenetic alterations occur as eukaryotes age. However, key questions remain, in particular, what are driving mechanisms and genomic changes that underlie the cellular phenotypes that characterize senescence and aging? Our hypothesis is that healthy aging involves homeostasis of the epigenomic landscape, which we refer to as chromostasis, and that chromostasis fails during aging, leading to tissue deterioration and to organismal death. Hence, genetic methods and pharmaco-therapeutics to enhance chromostasis are a prominent feature across all collaborative projects of this P01 application and in this Project 2. During the previous funding period we showed a key functional role of chromatin alterations in yeast replicative aging and massive chromatin alterations in mammalian senescence. In the next funding period we will explore and elucidate new chromatin regulatory pathways that alter genomic function in senescence and aging, leading to loss of chromostasis. In preliminary studies, we newly identified chromatin regulators whose reduction extends replicative lifespan, leading to new pathways that maintain epigenome and transcriptome fidelity during aging. We also discovered that nuclear disruption and shedding of LADs/chromatin into the cytoplasm during senescence and aging is perceived by a canonical cytoplasmic DNA sensing pathway, cGAS-STING, which in turn triggers cellular immunity pathways and the SASP (the senescence associated secretory phenotype) leading eventually to tissue damage during aging. To uncover the mechanisms and physiological importance of these new chromatin regulators and pathways in aging, we will carry out the following aims: 1. Investigate gene-internal cryptic transcriptional initiation during aging. We hypothesize that gene-internal transcriptional activation sites disrupt normal initiation at key longevity genes and lead to a global loss of transcriptional fidelity, contributing to reduction of chromostasis. (2) Investigate aging-associated upregulation of histone acetylation creating new enhancers. We hypothesize that dysregulated chromostasis licenses new enhancers during aging, leading to increased transcription of anti-longevity genes. (3) Investigate loss of chromatin integrity during aging triggering inflammation and autophagy of longevity chromatin regulators. Our preliminary findings show that LADs/chromatin in the cytoplasm triggers aging-promoting cellular immunity pathways via cGAS-STING. In the proposed studies, we will unravel the cGAS-STING pathway in promoting the SASP program in cellular senescence and the chronic inflammation associated with natural aging. This research will yield novel epigenetic mechanisms altering longevity, with potential for new therapeutic targets for intervention in age-related diseases and to extend healthy lifespan.