Regulatory Network Inference of Induced Senescent Midbrain Cell Types Reveals Cell Type-Specific Senescence-Associated Transcriptional Regulators

Abstract Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context of Parkinson’s Disease (PD). The characterization of classical hallmarks of senescence is a widely debated topic, whereby the context in which a senescence phenotype is being investigated, such as the cell type, the inducing stressor, and/or the model system, is an extremely important aspect to consider when defining a senescent cell. Here, we describe a cell type-specific profile of senescence through the investigation of various canonical senescence markers in five human midbrain cell lines using chronic 5-Bromodeoxyuridine (BrdU) treatment as a model of DNA damage-induced senescence. We used principal component analysis (PCA) and subsequent regulatory network inference to define both unique and common senescence profiles in the cell types investigated, as well as revealed senescence-associated transcriptional regulators (SATRs). Functional characterization of one of the identified regulators, transcription factor AP4 (TFAP4), further highlights the cell type-specificity of the expression of the various senescence hallmarks. Our data indicates that SATRs modulate cell type-specific profiles of induced senescence in key midbrain cell types that play an important role in the context of aging and PD.