Transcriptional network heterogeneity of cellular senescence in single-cell resolution

During the course of organismal lifespan, various stressors cause cells to permanently exit the cell cycle, in a process referred to as cellular senescence. These cells are thought to contribute to age-related functional decline. A remarkable feature of cellular senescence is the considerable heterogeneity between senescent cells and the regulatory programs that induce this cell state. Additionally, to what extent these features are conserved in non-mammalian vertebrates is largely unknown. Here, to address these challenges, we use the naturally short-lived turquoise killifish as a genetic model. We first characterize enhancer landscape and single cell transcriptomic to explore the regulatory network of senescence in fish. We further identify conserved and novel senescence-related enhancers, which might be driving the expression of senescence-related genes. Sequence analysis of senescence-related enhancer elements implicated the AP-1 transcription activator complex as a possible important mediator. Currently, we are developing an in-vitro platform to functionally explore our identified enhancers. The most promising enhancer elements will be further investigated in vivo using Killifish reporter lines and in vivo imaging which will allow us to identify novel, potentially vertebrate-conserved enhancer elements. Identifying molecular markers of senescence will provide important insight into the regulation and spatiotemporal dynamics of cellular senescence.