To understand inheritance patterns of health and disease, we must understand what information is passed between generations. There are a growing number of examples where some epigenetic modifications acquired during an individual’s lifetime are inherited from parent to offspring. This phenomenon is called transgenerational epigenetic inheritance (TEI) and could provide a mechanism for the inheritance of environmentally-acquired traits. The number of generations this inheritance persists, and the signal passed between generations remain unclear.
We are studying TEI in Caenorhabditis elegans. We have developed a system in which exposure to an environmental RNAi trigger induces robust TEI for multiple generations. To investigate the long-term dynamics of TEI, we followed epigenetic inheritance in different lineages of individual animals until the inheritance signal was exhausted. We show that animals display heterogeneous inheritance responses: inheritance lasts just a few generations in some lineages, but many more generations in others. We sequenced small RNAs in animals which inherited silencing and those which did not. Interestingly, we found that a particular class of small silencing RNAs thought to constitute the transgenerational signal did not correlate with inheritance, suggesting that other mechanisms are at play. We are now investigating a recently discovered class of RNA which has been associated with TEI, which may constitute the epigenetic signal inherited between generations. This class comprises RNAs 70-600 nucleotides in length with a long, untemplated 3' poly-UG tail, termed poly-UG (pUG) RNAs. Using our model of TEI, we characterise pUG RNAs in lineages displaying different TEI dynamics, namely 1) populations where inheritance persists and after it is exhausted, 2) lineages displaying weak vs strong inheritance, and 3) populations which are mutant in TEI factors including Argonaute proteins and chromatin modifiers. Together, we characterise the correlation between pUG RNAs and TEI to further understanding of TEI dynamics and heterogeneity between lineages.