Pioneer transcription factors in aging and neurodegeneration

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.