Diversity Supplement for Regulation of longevity through maintenance of transcription fidelity

通过维持转录保真度调节寿命的多样性补充

基本信息

批准号：
10403727
负责人：
Weiwei Dang
金额：
$ 8.4万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2024-04-30
项目状态：
已结题

项目摘要

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.

项目摘要衰老对人类疾病的发展和进展有深远的影响死亡率的原因，包括心血管疾病，糖尿病，神经退行性疾病，感染性疾病和癌症。异常的表观遗传改变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。这个长期目标项目是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，通过新的组蛋白突变寿命屏幕，我们发现组蛋白H3的三甲基化赖氨酸36（H3K36ME3）通过抑制基因内隐性转录来促进寿命。我们也显示了这种神秘的转录被认为是一种转录不忠的一种形式，随着酵母和蠕虫；抑制神秘转录的遗传操作延长了寿命。这些观察表明与年龄相关的隐性转录和由此产生的转录保真度的增加是进化保守的衰老原因。在拟议的项目中，我们将通过研究来检验这一假设 1）衰老期间隐性转录增加的原因； 2）隐性转录的抑制如何延伸寿命; 3）在较高的真核系统中衰老期间该途径的功能保护，包括蠕虫和哺乳动物成年干细胞。该项目研究了衰老的分子原因新颖的观点，并将导致发现新的表观遗传机制，可以用作衰老和与年龄有关的疾病的潜在治疗靶标。