12 The immune system regulates sperm RNAs to drive transgenerational epigenetic inheritance in mice

Abstract It was long assumed that sperm’s sole function was to transport the paternal genome. However, it is now increasingly understood that the male gamete also transmits molecules, including RNAs, to the egg during fertilization, leading to non-genetically inherited phenotypes in offspring. In particular, small non-coding RNAs have been identified as key transmitters of paternal epigenetic information in some of the best-characterized examples of transgenerational epigenetic inheritance, such as RNA interference (RNAi) in C. elegans, and paramutation in plants and mice. Furthermore, in rodents, sperm small RNAs have been shown to causally transmit paternal epigenetically inherited phenotypes. In mice, multiple studies have demonstrated that sperm small RNAs are crucial for embryonic development. Despite these findings, the molecular processes that enable sperm RNAs to act as heritable information—altering developmental trajectories and inducing adult phenotypes—remain largely unknown in any organism. Using a variety of model systems, including mice, C. elegans, and ­embryonic stem cells, we are investigating the molecular mechanisms by which sperm small RNAs program embryonic development and transmit non-genetically inherited phenotypes to offspring. Additionally, we recently discovered that, in mice, the immune system and microbiome can regulate the accumulation of small RNAs in sperm. This occurs through the regulation of RNA packaging into extracellular vesicles in the epididymis, which then fuse with sperm, delivering their RNA cargo. Fascinatingly, this process leads to the ­transmission of epigenetically inherited phenotypes both intergenerationally (to F1 progeny) and transgenerationally (to F2 progeny and beyond).