美国国立卫生研究院Keiko Ozato等研究人员合作发现，IRF8在后天小胶质细胞中定义表观遗传图谱，从而引导它们的转录组程序。相关论文于2024年9月23日在线发表在《自然—免疫学》杂志上。

研究人员证明了干扰素调节因子8（IRF8）与Sall1和PU.1逐步结合后天小胶质细胞的增强子区域，结合在第14天达到最大值。IRF8结合与染色质可及性的逐步增加相关，这一过程先于小胶质细胞特异性转录组的启动。持续和后天的Irf8缺失导致小胶质细胞身份丧失，和病理相关小胶质细胞（DAM）样基因的获得。

单细胞RNA测序和单细胞可接近染色质测序的综合分析显示了染色质可及性与转录组之间在单细胞水平上的相关性。IRF8还对小胶质细胞特异性DNA甲基化模式的形成是必需的。

在5xFAD模型中，持续和后天的Irf8缺失减少了小胶质细胞与淀粉样β斑块的相互作用以及斑块的大小，从而减轻了神经元丧失。总之，IRF8设定了表观遗传图谱，这对后天小胶质细胞的基因表达是必需的。

据悉，小胶质细胞是大脑中的固有免疫细胞。转录因子IRF8（干扰素调节因子8）在小胶质细胞中高表达，但其在后天小胶质细胞发育中的作用尚不清楚。

附：英文原文

Title: IRF8 defines the epigenetic landscape in postnatal microglia, thereby directing their transcriptome programs

Author: Saeki, Keita, Pan, Richard, Lee, Eunju, Kurotaki, Daisuke, Ozato, Keiko

Issue&Volume: 2024-09-23

Abstract: 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.

DOI: 10.1038/s41590-024-01962-2

Source: https://www.nature.com/articles/s41590-024-01962-2