IRF8 configures enhancer landscape in postnatal microglia and directs microglia specific transcriptional programs.

Microglia are innate immune cells in the brain. Transcription factor IRF8 is highly expressed in microglia. However, its role in postnatal microglia development and the mechanism of action is unknown. We demonstrate here that IRF8 binds to enhancer regions of postnatal microglia in a stepwise fashion reaching a maximum after day 14, which coincided with the initiation of microglia function. Constitutive Irf8 deletion led to the loss of microglia identity gene expression and aberrant induction of Alzheimer's disease and neurodegeneration associated genes. Conditional Irf8 deletion in adult microglia showed similar transcriptome profiles, revealing the requirement of continuous IRF8 expression. Additional genome-wide analyses showed IRF8 is critical for setting microglia-specific chromatin accessibility and DNA methylation patterns. Lastly, in the 5xFAD mouse AD model, Irf8 deletion lessened the formation and spread of amyloidβ plaques, thereby reducing neuronal loss. Together, IRF8 sets the microglia epigenome landscape, required for eliciting microglia identity and function.