Description
Virtually all cells in multicellular organisms share the same genome. The combinatorial activity of transcription factors (TFs), master regulators of cell identity, enables the establishment of distinct cell types, which undergo substantial functional shifts across life. Until recently the process of how genes change activity from birth to adulthood and into old age was largely unknown.
The Nefzger Lab has mapped chromatin and transcriptional changes across >45 mouse and human cell types and uncovered a conserved mechanism that links organismal maturation with aging (Cell Metabolism; Patrick et al., 2024, PMID: 38959897). We identified the transcription factor AP-1 as a key driver of this shared trajectory. During maturation, AP-1 activates adult gene programs while diverting cell-identity TFs away from developmental regulatory elements as growth slows and tissues mature. Beyond early adulthood, stress- and inflammation-induced AP-1 activity continues to open chromatin which actively shuts down “youthful” gene programs by hijacking this developmental mechanism.
Mechanistically, AP-1-linked chromatin opening exposes competing TF binding sites, including sites for essential identity-defining factors, drawing these TFs away from their canonical binding sites toward newly activated chromatin and thereby remodeling cell identity. Our work thus reframes cell aging not as random drift, but as a predictable TF-network remodelling process in which escalating AP-1 activity progressively reconfigures cell identity to drive decline.
The current project will critically expand our mechanistic understanding of this process by mapping life-stage-specific TF co-factor partnerships and determining how these change between maturation and aging. In parallel, we will study diverse layers of epigenetic regulation to identify safeguards that keep adult and late-life gene regulatory elements silenced early in life. This will reveal how AP-1 binding-site-rich gene regulatory elements are repressed prior to their progressive activation during maturation. Together, by combining TF co-factor partnership maps with multi-layer epigenetic profiling, we will extend our previous work on chromatin accessibility into a broad framework of how gene regulation is remodelled during maturation to explain its predictable deregulation in aging. This will also inform intervention strategies to preserve cell and tissue function with age.
Results
The project start date is 1 November 2025