Institute of Comparative Medicine, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, China.
College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China.
Int J Mol Sci. 2023 Jan 25;24(3):2394. doi: 10.3390/ijms24032394.
Alveolar macrophages (AMs) form the first defense line against various respiratory pathogens, and their immune response has a profound impact on the outcome of respiratory infection. Enhancer of zeste homolog 2 (EZH2), which catalyzes the trimethylation of H3K27 for epigenetic repression, has gained increasing attention for its immune regulation function, yet its exact function in AMs remains largely obscure. Using porcine 3D4/21 AM cells as a model, we characterized the transcriptomic and epigenomic alterations after the inhibition of EZH2. We found that the inhibition of EZH2 causes transcriptional activation of numerous immune genes and inhibits the subsequent infection by influenza A virus. Interestingly, specific families of transposable elements, particularly endogenous retrovirus elements (ERVs) and LINEs which belong to retrotransposons, also become derepressed. While some of the derepressed ERV families are pig-specific, a few ancestral families are known to be under EZH2-mediated repression in humans. Given that derepression of ERVs can promote innate immune activation through "viral mimicry", we speculate that ERVs may also contribute to the coinciding immune activation in AMs after the inhibition of EZH2. Overall, this study improves the understanding of the EZH2-related immune regulation in AMs and provides novel insights into the epigenetic regulation of retrotransposons in pigs.
肺泡巨噬细胞 (AMs) 构成了抵御各种呼吸道病原体的第一道防线，其免疫反应对呼吸道感染的结果有深远影响。增强子的锌指蛋白 2（EZH2）通过组蛋白 H3K27 的三甲基化来催化表观遗传抑制，因其免疫调节功能而受到越来越多的关注，但它在 AMs 中的确切功能在很大程度上仍不清楚。我们使用猪 3D4/21 AM 细胞作为模型，研究了 EZH2 抑制后转录组和表观基因组的改变。我们发现，EZH2 的抑制导致大量免疫基因的转录激活，并抑制随后的甲型流感病毒感染。有趣的是，特定的转座元件家族，特别是属于逆转座子的内源性逆转录病毒元件 (ERVs) 和 LINEs，也被去抑制。虽然一些去抑制的 ERV 家族是猪特有的，但有几个已知的家族在人类中受到 EZH2 介导的抑制。鉴于 ERV 的去抑制可以通过“病毒模拟”促进先天免疫激活，我们推测 ERV 也可能有助于 EZH2 抑制后 AMs 中同时发生的免疫激活。总的来说，这项研究提高了我们对 AMs 中 EZH2 相关免疫调节的理解，并为猪中转座子的表观遗传调控提供了新的见解。
