Liu Fang, Wang Qingyao, Xiong Jun, Wang Mengqi, Zhou Hanlin, Xiao Yi
Institute of Life Sciences, Zunyi Medical University, Zunyi, Guizhou, 563000, China.
College of Basic Medicine, Zunyi Medical University, Zunyi, Guizhou, 563000, China.
Cell Commun Signal. 2025 Sep 24;23(1):397. doi: 10.1186/s12964-025-02386-7.
S-adenosylmethionine (SAM), is a ubiquitous cofactor necessary for methyltransferase reactions. Deficiency in SAM results in dysregulation of crucial methylation and cellular dysfunction. SAM promotes innate immunity via histone H3K4me3 complex, raising the question of whether SAM supplementation in the parental generation could be reprogrammed histone modifications in offspring and thereby affect the innate immunity of descendants. In this study, we fed Caenorhabditis elegans with SAM, which led to enhance innate immunity. Furthermore, this enhancement is capable of transmitting the phenotype to subsequent generations. Transcriptome sequencing and GO functional enrichment analysis revealed that SAM induced the expression of genes involved in immune responses and IRE-1-mediated endoplasmic reticulum unfolded protein response (UPR), revealing those genes were required for transgenerational innate immunity enhancement. Additionally, histone H3K4me3 marked immune response genes and IRE-1-mediated UPR genes and promoted their transcription response to multigenerational innate immunity enhancement effects. Our findings indicate that the endoplasmic reticulum unfolded protein response (UPR) in parental somatic cells mediates the establishment of epigenetic memory, which is preserved through the histone H3K4me3 complex in the germline across generations. Surprisingly, the transgenerational epigenetic inheritance (TEI) of the immune response induced by a SAM diet occurs independently of small RNAs. These findings offer valuable insights into the mechanisms driving multigenerational innate immunity reprogramming and clarify the effects of SAM supplementation.
S-腺苷甲硫氨酸（SAM）是甲基转移酶反应所必需的一种普遍存在的辅因子。SAM缺乏会导致关键甲基化失调和细胞功能障碍。SAM通过组蛋白H3K4me3复合物促进先天免疫，这就引发了一个问题，即亲代补充SAM是否会重新编程后代的组蛋白修饰，从而影响后代的先天免疫。在本研究中，我们用SAM喂养秀丽隐杆线虫，这导致其先天免疫增强。此外，这种增强能够将表型传递给后代。转录组测序和GO功能富集分析表明，SAM诱导了参与免疫反应和IRE-1介导的内质网未折叠蛋白反应（UPR）的基因表达，揭示这些基因是跨代先天免疫增强所必需的。此外，组蛋白H3K4me3标记了免疫反应基因和IRE-1介导的UPR基因，并促进它们对多代先天免疫增强效应的转录反应。我们的研究结果表明，亲代体细胞中的内质网未折叠蛋白反应（UPR）介导了表观遗传记忆的建立，这种记忆通过生殖系中的组蛋白H3K4me3复合物代代相传。令人惊讶的是，SAM饮食诱导的免疫反应的跨代表观遗传继承（TEI）独立于小RNA发生。这些发现为驱动多代先天免疫重编程的机制提供了有价值的见解，并阐明了SAM补充的作用。
