The retrotransposable element-silencing factor Daxx controls microglia identity and function in the adult brain

Death domain-associated protein (Daxx) is one of the two main H3.3 chaperones in mammalian cells and acts as key repressor of RTEs of viral origin. In the present study, we found that Daxx is an IFN-stimulated gene mediating repression of RTEs and IFN-stimulated genes (ISGs) upon inflammatory stimuli in microglia. Using both bulk and single-cell genomics, we demonstrated that shortly after Daxx loss microglia displayed co-expression of DNA damage/p53, IFN/developmental and DAM-like signatures, suggesting lowering of the epigenetic barrier and increased plasticity. With time, Daxx-deficient microglia become restricted to a DAM-like/ApoeHIGH profile, associated with decreased synaptic puncta and altered behavior. Finally, brains from older microglia-specific Daxx KO mice accumulate ApoE protein along with lysosomal markers. Together, our data revealed a role of Daxx in maintenance of the homeostatic state of microglia in the adult brain, with implications for our understanding of the relationship between loss of epigenetic barriers and neuroinflammation and its potential implications for brain function and aging.