Transgenerational epigenetic inheritance: mechanisms and consequences for metabolism and ageing

Epigenetic changes that occur during the lifetime of an individual are generally not inherited by the next generation, as this could subvert epigenetic reprogramming events needed to reinstate totipotency. Yet, some genomic elements remain incompletely reprogrammed, and may thus represent a key genomic vehicle for transgenerational epigenetic inheritance47. Transgenerational inheritance requires that the germline remembers exposure to environmental changes and allows for these to be inherited to the next generation(s). Nutritional stress can mediate transgenerational memory through histone marks and small RNA pathways in invertebrates and DNA methylation changes in mice48,49. As observed in many studies, the inheritance mediated by epigenetic modifications reverts back to wild-type after one or a few generations. However, some epigenetic changes can lead to more permanent genome rearrangements, when coupled to genomic instability. For example, nutritional stress can lead to instability of high copy number ribosomal DNA (rDNA), resulting in copy number variation (CNV) at rDNA loci. There are many key aspects that remain unresolved in the field and this Objective tackles two essential questions: firstly, what are the mechanisms by which epigenetic reprogramming normally returns cells to a naïve and totipotent stage and could these mechanisms thereby mediate transgenerational inheritance upon experimental manipulation. Secondly, can, and if so how could, stressors such as age and nutrition contribute to inheritance by modifying CNV through gametes with consequences for metabolism and ageing in subsequent generations.