Pioneer transcription factors in aging and neurodegeneration

项目摘要 已经发现许多转录调节因子调节衰老的标志。在以前的工作中， 我们发现FOXO转录调节因子家族与健康衰老有关 跨物种，直接调节靶基因的保守网络。在小鼠中，FOXO是中枢调节器， 干细胞在衰老过程中的体内平衡，对组织的完整性至关重要。在人类中，FOXO 3基因座中的SNP 与长寿有关，FOXO的上游调节因子，胰岛素/IGF信号传导必须紧密地 以保持健康的衰老。然而，我们仍然缺乏对FOXO如何在 染色质水平，以及它们的活性在衰老过程中和神经变性的背景下如何改变。在 在初步工作中，我们首次确定了人体细胞中FOXO 3靶点的直接网络，并发现 FOXO作为先驱因子发挥作用，部署转录调节因子的二级网络， 他们的目标基因网络在这里，我们将解决这一关键问题的机制， 活动，其异质性，以及它如何在衰老和阿尔茨海默病的背景下变化。 这项工作的完成将揭示染色质水平的变化，影响活动的因素，反 衰老和神经变性，这可能导致改善相关病理的策略。

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.