Regulation of longevity through maintenance of transcription fidelity

通过维持转录保真度来调节寿命

• 批准号: 9238266
• 负责人: Weiwei Dang
• 金额: $ 33.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9238266
• 关键词: Affect; Age; Aging; Aging-Related Process; Caenorhabditis elegans; Caloric Restriction; Cardiovascular Diseases; Cells; Chromatin; Code; Collaborations; Communicable Diseases; Data; Data Correlations; Dependency; Development; Diabetes Mellitus; Disease; Elements; Epigenetic Process; Eukaryota; Future; Gene Expression; Generations; Genes; Genetic; Genetic Epistasis; Genetic Transcription; Genetic screening method; Goals; Hematopoietic stem cells; Histone H3; Histones; Homologous Gene; Human; Knowledge; Length; Link; Location; Longevity; Lysine; Maintenance; Malignant Neoplasms; Maps; Mediating; Mesenchymal Stem Cells; Modification; Molecular; Mus; Mutation; Neurodegenerative Disorders; PRKAG2 gene; Pathway interactions; Pattern; Phenotype; Physiological; Regulation; Regulatory Pathway; Research; Resolution; Role; Supporting Cell; System; Testing; Transcript; Transcription Elongation; Transcription Initiation; Whole Organism; Yeasts; adult stem cell; age related; aged; base; cell age; design; embryonic stem cell; experimental study; functional decline; genetic manipulation; healthy aging; histone acetyltransferase; histone methylation; histone modification; human disease; knock-down; mortality; mutant; novel; novel therapeutics; therapeutic target; transcriptome sequencing

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.

项目摘要 老龄化对人类疾病的发展和进展有着深远的影响， 死亡原因，包括心血管疾病、糖尿病、神经退行性疾病、传染病、 疾病和癌症。异常的表观遗传改变被归因于许多年龄的发展- 相关疾病，最近发现与衰老本身密切相关。长期目标是 该项目旨在确定表观遗传和染色质调节途径在衰老调节中的作用。 最近，通过一种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（H3 K36 me 3）通过抑制基因内隐蔽转录促进长寿。我们还表明 被认为是转录不忠实的一种形式的神秘转录，在酵母和 蠕虫;基因操纵抑制隐蔽转录延长寿命。这些观察结果表明 与年龄相关的隐性转录增加以及由此导致的转录保真度丧失， 进化上保守的衰老原因。在本项目中，我们将通过调查来验证这一假设。 1)衰老过程中隐性转录增加的原因; 2）隐性转录的抑制如何延伸 寿命;和3）在高等真核系统中，该途径在衰老期间的功能保守， 包括蠕虫和哺乳动物成体干细胞。这个项目从一个角度研究了衰老的分子原因。 新的观点，并将导致发现新的衰老表观遗传机制，可以作为 衰老和年龄相关疾病的潜在治疗靶点。