Regulation of longevity through maintenance of transcription fidelity

项目总结 老龄化对人类主要疾病的发展和进展有深远的影响 死亡原因，包括心血管疾病、糖尿病、神经退行性疾病、传染性疾病 疾病和癌症。异常的表观遗传变化被归因于许多年龄的发展- 相关疾病，最近被发现与衰老本身密切相关。这样做的长期目标是 该项目旨在确定表观遗传和染色质调节通路在衰老调节中的作用。 最近，通过一个新的组蛋白突变体寿命筛选，我们发现组蛋白H3的三甲基化在 赖氨酸36(H3K36me3)通过抑制基因内隐含转录而延长寿命。我们还展示了 这种隐秘的转录被认为是转录不忠的一种形式，在酵母和酵母中随着年龄的增长而增加 蠕虫；抑制隐秘转录的基因操作延长了寿命。这些观察结果表明 与年龄相关的神秘转录的增加和由此导致的转录保真度的丧失是 进化上保守的衰老原因。在提议的项目中，我们将通过调查 1)衰老过程中隐藏转录增加的原因；2)隐藏转录的抑制是如何延伸的 寿命；以及3)在高等真核系统中该途径在衰老过程中的功能保守， 包括蠕虫和哺乳动物成体干细胞。这个项目研究了衰老的分子原因。 新的视角，并将导致发现新的表观遗传衰老机制，这可能是 老龄化和老年相关疾病的潜在治疗靶点。

PROJECT SUMMARY Aging has profound impacts on the development and progression of human diseases that are principal causes of mortality, including cardiovascular diseases, diabetes, neurodegenerative diseases, infectious diseases and cancer. Aberrant epigenetic alterations have been attributed to the development of many age- related disorders and have recently been found to be closely linked to aging itself. The long-term goal of this project is to determine the roles of epigenetic and chromatin regulatory pathways in the regulation of aging. Recently, through a novel histone mutant lifespan screen, we found that tri-methylation of histone H3 at lysine 36 (H3K36me3) promotes longevity by suppressing intragenic cryptic transcription. We have also shown that cryptic transcription, considered a form of transcription infidelity, increases with age in both yeast and worms; genetic manipulations that suppress cryptic transcription extend lifespan. These observations suggest that the age-associated increases in cryptic transcription and the resulting loss of transcription fidelity are evolutionarily conserved causes of aging. In the proposed project, we will test this hypothesis by investigating 1) the cause of increased cryptic transcription during aging; 2) how suppression of cryptic transcription extends lifespan; and 3) the functional conservation of this pathway during aging in higher eukaryotic systems, including worms and mammalian adult stem cells. This project examines the molecular causes of aging from a novel perspective and will lead to the discovery of new epigenetic mechanism of aging that could serve as potential therapeutic targets of aging and age-related diseases.