Purinergic exposure induces epigenomic and transcriptomic-mediated preconditioning resembling epilepsy-associated microglial states

Microglia play a crucial role in a range of neuropathologies through exacerbated activation. Microglial inflammatory responses can be influenced by prior exposures to noxious stimuli, like increased levels of extracellular adenosine and ATP. These are characteristic of brain insults like epileptic seizures and could potentially shape subsequent responses through epigenetic regulation. We investigated DNA methylation and expression changes in human microglia-like cells differentiated from monocytes following ATP-mediated preconditioning. We demonstrate that microglia-like cells display homeostatic microglial features, shown by surface markers, transcriptome, and DNA methylome. After exposure to ATP, TLR-mediated activation leads to an exacerbated pro-inflammatory response. These changes are accompanied by methylation and transcriptional reprogramming associated with enhanced immune-related functions. The reprogramming associated with ATP-mediated preconditioning leads to profiles found in microglial subsets linked to epilepsy. Purine-driven microglia immune preconditioning drives epigenetic and transcriptional changes that could contribute to altered functions of microglia during seizure development and progression. [Display omitted] •Microglia-like cells replicate microglial transcriptome and DNA methylome•Purinergic preconditioning promotes enhanced pro-inflammatory response•Methylation and transcription of inflammatory genes are altered by ATP pre-exposure•ATP-related expression changes mimic microglial population expanded in epilepsy Microglia; Purines; Epilepsy; Epigenetics; Transcriptomics