Pioneer transcription factors in aging and neurodegeneration

项目总结 已经发现了许多转录调控因子来调节衰老的特征。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，直接调控一个保守的目标基因网络。在小鼠中，FOXO是中央调节器 干细胞在衰老过程中的动态平衡，对组织的完整性至关重要。在人类中，FOX03基因座上的SNPs 与长寿有关，作为FOXO的上游调节因子，胰岛素/IGF信号必须紧密地 监管，以保持健康的衰老。然而，我们仍然缺乏对FOXO在 染色质水平，以及它们的活性在衰老和神经退化的背景下如何改变。在……里面 前期工作中，我们首次鉴定出FOXO_3靶标在人类细胞中的直接网络，并发现 FOXO发挥先锋因子的作用，部署转录调控的二级网络，以扩展 它们的目标基因网络。在这里，我们将解决这个关键的问题，即先驱者背后的机制 活动，其异质性，以及它如何在老龄化和阿尔茨海默病的背景下发生变化。 这项工作的完成将揭示染色质水平的变化，这些变化会影响对抗因子的活性 衰老和神经退化，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.