Pioneer transcription factors in aging and neurodegeneration

衰老和神经退行性疾病中的先驱转录因子

基本信息

批准号：
10463835
负责人：
Ashley E Webb
金额：
$ 45.57万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10463835
关键词：
ATAC-seq Ablation Address Aging Alzheimer&apos s Disease Animal Model Biological Assay Brain Caenorhabditis elegans Cell physiology Cells Cellular Stress ChIP-seq Chromatin Chromatin Remodeling Factor Data Disease Disease Progression Etiology FOXO3A gene Family Future Gene Expression Genes Genetic Transcription Genomics Goals Health Homeostasis Human Individual Insulin Intervention Invertebrates Lead Link Longevity Mediating Meta-Analysis Metabolism Mus Nature Nerve Degeneration Neurodegenerative Disorders Pathology Pathway interactions Physiological Population Publishing Quality Control Rodent Role Signal Transduction Single Nucleotide Polymorphism Site Testing Time Tissues Transcription Factor AP-1 Work age effect age related aging brain aging population biological adaptation to stress chromatin remodeling epigenomics functional genomics gene network genome-wide healthy aging improved induced pluripotent stem cell insight multiple omics nerve stem cell preservation prevent programs stem cell homeostasis stem cell model therapeutic candidate therapeutic target transcription factor transcriptome sequencing

项目摘要

PROJECT SUMMARY A number of transcriptional regulators have been found to regulate the hallmarks of aging. In previous work, we found that the FOXO family of transcriptional regulators, which have been implicated in healthy aging across species, directly regulate a conserved network of target genes. In mice, FOXOs are central regulators of stem cell homeostasis during aging and are critical for tissue integrity. In humans, SNPs in the FOXO3 locus have been linked to longevity, and the upstream regulator of FOXO’s, insulin/IGF signaling must be tightly regulated to preserve healthy aging. Yet, we still lack an understanding of how FOXOs function at the chromatin level, and how their activity is altered during aging and in the context of neurodegeneration. In preliminary work, we identified for the first time the direct network of FOXO3 targets in human cells, and found that FOXOs function as pioneer factors to deploy a secondary network of transcriptional regulators to extend their target gene network. Here, we will address this critical question of the mechanisms underlying the pioneer activity, its heterogeneous nature, and how it changes in the context of aging and Alzheimer’s Disease. Completion of this work will reveal the chromatin-level changes that influence the activity of factors that counter aging and neurodegeneration, which may lead to strategies to improve associated pathologies.

项目摘要已经发现许多转录调节器可以调节衰老的标志。在以前的工作中我们发现，在健康衰老中隐含的转录调节剂家族跨物种，直接调节靶基因的保守网络。在老鼠中，福克斯是中央监管机构衰老过程中干细胞稳态的体内平衡，对于组织完整性至关重要。在人类中，foxo3基因座的SNP 与长寿相关，Foxo的上游调节器，胰岛素/IGF信号必须紧密受监管以保留健康的衰老。但是，我们仍然对福克斯在染色质水平，以及在衰老和神经退行性的背景下如何改变其活性。在初步工作，我们首次确定了人类细胞中FOXO3目标的直接网络，并发现 Foxos是部署转录调节器的辅助网络以扩展的先驱因素他们的目标基因网络。在这里，我们将解决这个先驱基础机制的关键问题活动，异质性质以及它在衰老和阿尔茨海默氏病的背景下如何变化。这项工作的完成将揭示染色质级的变化，这些变化影响了反应因素的活动衰老和神经变性，这可能导致改善相关病理的策略。