Parental S-adenosylmethionine diet defines offspring immune response via histone H3K4me3 complex and Endoplasmic Reticulum UPR.

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(ER)), revealing those genes were required for transgenerational innate immunity enhancement. Additionally, histone H3K4me3 marked immune response genes and IRE-1-mediated UPR(ER) genes and promoted their transcription response to multigenerational innate immunity enhancement effects. Our findings indicate that the endoplasmic reticulum unfolded protein response (UPR(ER)) 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.