Saeki Keita, Pan Richard, Lee Eunju, Kurotaki Daisuke, Ozato Keiko
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892.
MD-PhD Candidate in Neurobiology and Behavior, Columbia University, School of Medicine, New York, NY.
bioRxiv. 2024 Jul 1:2023.06.25.546453. doi: 10.1101/2023.06.25.546453.
Microglia are innate immune cells in the brain. Transcription factor IRF8 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 deletion led to a loss of microglia identity and gain of disease-associated microglia-like genes. Combined analysis of scRNA-seq and 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. Lastly, in the 5xFAD model, constitutive and postnatal deletion reduced the interaction of microglia with Aβ 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固有免疫细胞。转录因子IRF8在小胶质细胞中高度表达。然而，其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.1一起逐步结合到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的结合与染色质可及性的逐步增加相关，这先于小胶质细胞特异性转录组的起始。组成性和出生后缺失导致小胶质细胞身份丧失和疾病相关小胶质细胞样基因的获得。对scRNA-seq和scATAC-seq的联合分析揭示了单细胞水平上染色质可及性与转录组之间的相关性。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，组成性和出生后缺失减少了小胶质细胞与Aβ斑块的相互作用以及斑块的大小，减轻了神经元损失。总之，IRF8设定了表观遗传格局，这是出生后小胶质细胞基因表达所必需的。
