Microglia are innate immune cells in the brain. Transcription factor IRF8 (interferon regulatory factor 8) is highly expressed in microglia. However, its role in postnatal microglia development is unknown. We demonstrate that IRF8 binds stepwise to enhancer regions of postnatal microglia along with Sall1 and PU.1, reaching a maximum after day 14. IRF8 binding correlated with a stepwise increase in chromatin accessibility, which preceded the initiation of microglia-specific transcriptome. Constitutive and postnatal Irf8 deletion led to a loss of microglia identity and gain of disease-associated microglia (DAM)-like genes. Combined analysis of single-cell (sc)RNA sequencing and single-cell transposase-accessible chromatin with sequencing (scATAC–seq) revealed a correlation between chromatin accessibility and transcriptome at a single-cell level. IRF8 was also required for microglia-specific DNA methylation patterns. Last, in the 5xFAD model, constitutive and postnatal Irf8 deletion reduced the interaction of microglia with amyloidβ plaques and the size of plaques, lessening neuronal loss. Together, IRF8 sets the epigenetic landscape, which is required for postnatal microglia gene expression.

小胶质细胞是大脑中的先天免疫细胞。转录因子 IRF8 （干扰素调节因子 8） 在小胶质细胞中高度表达。然而，它在出生后小胶质细胞发育中的作用尚不清楚。我们证明 IRF8 与 Sall1 和 PU.1 一起逐步结合出生后小胶质细胞的增强子区域，在第 14 天后达到最大值。IRF8 结合与染色质可及性的逐步增加相关，这发生在小胶质细胞特异性转录组开始之前。组成型和出生后 Irf8 缺失导致小胶质细胞身份丧失和疾病相关小胶质细胞 （DAM） 样基因的增加。单细胞 （sc） RNA 测序和单细胞转座酶可及染色质与测序 （scATAC-seq） 的联合分析揭示了染色质可及性与转录组在单细胞水平上的相关性。IRF8 也是小胶质细胞特异性 DNA 甲基化模式所必需的。最后，在 5xFAD 模型中，组成型和出生后 Irf8 缺失减少了小胶质细胞与淀粉样蛋白 β 斑块的相互作用以及斑块的大小，减少了神经元丢失。IRF8 共同设置了出生后小胶质细胞基因表达所需的表观遗传景观。