SETDB1 modulates neuroinflammation in the mouse cortex by regulating neuronal P2rx7 expression

Neuroinflammation is a pivotal feature of neuropsychiatric conditions, yet the brain-intrinsic epigenetic mechanisms initiating this response are not fully understood. In this study, we show that loss of the histone H3K9me3 methyltransferase SETDB1 in excitatory neurons (Setdb1-CK-cKO) triggers endogenous retrovirus (ERV) activation and neuroinflammation in the mouse cortex. ERV activation occurs in both neurons and astrocytes, leading to the emergence of a distinct reactive astrocyte population with increased expression of inflammatory chemokines and cytokines. Mechanistically, we identify the purinergic receptor gene P2rx7 as a direct target of SETDB1. We characterize a novel enhancer in the P2rx7 first intron that is epigenetically silenced by SETDB1; loss of SETDB1 results in increased chromatin accessibility and aberrant P2rx7 overexpression. This epigenetic regulatory mechanism is conserved between mouse and human. Moreover, genetic ablation of P2rx7 in Setdb1-CK-cKO mice partially reverses ERV activation and inflammatory gene dysregulation, and attenuates synaptic dysfunction. These findings provide new mechanistic insight into the epigenetic regulation of P2X7R signaling in controlling endogenous neuroinflammatory responses in the central nervous system.